Publications

Abstract

Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past.

Abstract

Dit artikel is de inleiding op het direct hierna volgende (Oonk e.a. 2022) waar een nieuw praktijkmodel over het ontstaan en ontwikkeling van stotteren wordt voorgesteld.

In de dagelijkse praktijk van vooral Nederlandstalige logopedisten (-stottertherapeuten) is tot nu toe veel gebruik gemaakt van het klinische werkmodel van Bertens (1994; 2017). Dit model gaat uit van een primaire neuromusculaire timingsstoornis, welke zich niet alleen uit in het spreken, maar ook in algemene zin aanwezig is. Dit model echter, is aan revisie toe. Volgens de recente literatuur is de algemene aard van die timingstoornis niet bewezen, en zijn er veel vroegere (meer primaire) factoren aantoonbaar van belang bij het ontstaan van stotteren, met name in de genetica en in de neurologie. In dit artikel wordt deze literatuur kort samengevat, alsmede worden enkele recente modellen omschreven. Met name regulatie en terugkoppeling krijgen in recente modellen meer aandacht. Er is geen volledigheid nagestreefd, maar dit artikel is meer een tutoriale opmaat voor het hierna te presenteren model.
(This article serves as an introduction to the accompanying paper, in which a new clinical
model of the origin and development of stuttering is presented (Oonk e.a., 2022).
In their clinical practice, Dutch speech language pathologists still tend to use the
clinical model proposed by Bertens (1994; 2017). This model explains stuttering as de-
veloping from a primary neuromuscular timing deficit, which manifests itself not only
in speech, but in more general behaviour as well. In our opinion, this model needs to be
updated and revised based on current scientific and clinical knowledge. There is littleevidence for the general timing deficit in Bertens’ model and, moreover, several more
fundamental factors, especially those related to genetics and neural processes, that have
an important role in the onset of stuttering have been reported. This paper provides a
review and summary of these recent data, and several newer models are described. An
important aspect of these models is the importance given to processes of regulation
and feedback. An exhaustive overview of the existing literature has not been strived for
but it is hoped that this paper will serve as a useful introduction to the clinical model
presented in the accompanying paper.)

Abstract

Aesthetic chills, broadly defined as a somatic marker of peak emotional-hedonic responses, are experienced by individuals across a variety of human cultures. Yet individuals vary widely in the propensity of feeling them. These individual differences have been studied in relation to demographics, personality, and neurobiological and physiological factors, but no study to date has explored the genetic etiological sources of variation. To partition genetic and environmental sources of variation in the propensity of feeling aesthetic chills, we fitted a biometrical genetic model to data from 14127 twins (from 8995 pairs), collected by the Netherlands Twin Register. Both genetic and unique environmental factors accounted for variance in aesthetic chills, with heritability estimated at .36 ([.33, .39] 95% CI). We found females more prone than males to report feeling aesthetic chills. However, a test for genotype x sex interaction did not show evidence that heritability differs between sexes. We thus show that the propensity of feeling aesthetic chills is not shaped by nurture alone, but it also reflects underlying genetic propensities.Competing Interest StatementThe authors have declared no competing interest.

Abstract

Purpose

Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants.
Methods

We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments.
Results

We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity.
Conclusion

Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.

Abstract

Aim

To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date.
Method

Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment.
Results

A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18–93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7–17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%).
Interpretation

The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies.

Abstract

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

Abstract

The current study presents an agent-based model which simulates the innovation and
competition among lexical items in cases of language contact. It is inspired by relatively
recent historical cases in which the linguistic ecology and sociohistorical context are highly complex. Pidgin and creole genesis offers an opportunity to obtain linguistic facts, social dynamics, and historical demography in a highly segregated society. This provides a solid ground for researching the interaction of populations with different pre-existing language systems, and how different factors contribute to the genesis of the lexicon of a newly generated mixed language. We take into consideration the population dynamics and structures, as well as a distribution of word frequencies related to language use, in order to study how social factors may affect the developmental trajectory of languages. Focusing on the case of Sranan in Suriname, our study shows that it is possible to account for the
composition of its core lexicon in relation to different social groups, contact patterns, and
large population movements.

Abstract

Lateralization is a fundamental characteristic of many behaviors and the organization of the brain, and atypical lateralization has been suggested to be linked to various brain-related disorders such as autism and schizophrenia. Right-handedness is one of the most prominent markers of human behavioural lateralization, yet its neurobiological basis remains to be determined. Here, we present a large-scale analysis of handedness, as measured by self-reported direction of hand preference, and its variability related to brain structural and functional organization in the UK Biobank (N = 36,024). A multivariate machine learning approach with multi-modalities of brain imaging data was adopted, to reveal how well brain imaging features could predict individual's handedness (i.e., right-handedness vs. non-right-handedness) and further identify the top brain signatures that contributed to the prediction. Overall, the results showed a good prediction performance, with an area under the receiver operating characteristic curve (AUROC) score of up to 0.72, driven largely by resting-state functional measures. Virtual lesion analysis and large-scale decoding analysis suggested that the brain networks with the highest importance in the prediction showed functional relevance to hand movement and several higher-level cognitive functions including language, arithmetic, and social interaction. Genetic analyses of contributions of common DNA polymorphisms to the imaging-derived handedness prediction score showed a significant heritability (h2=7.55%, p <0.001) that was similar to and slightly higher than that for the behavioural measure itself (h2=6.74%, p <0.001). The genetic correlation between the two was high (rg=0.71), suggesting that the imaging-derived score could be used as a surrogate in genetic studies where the behavioural measure is not available. This large-scale study using multimodal brain imaging and multivariate machine learning has shed new light on the neural correlates of human handedness.

Abstract

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns.

Abstract

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

Abstract

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Abstract

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to infer age‐related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta‐analysis and one‐way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Abstract

Large pretrained language models (PreLMs) are rev-olutionizing natural language processing across all benchmarks. However, their sheer size is prohibitive for small laboratories or for deployment on mobile devices. Approaches like pruning and distillation reduce the model size but typically retain the same model architecture. In contrast, we explore distilling PreLMs into a different, more efficient architecture, Continual Multiplication of Words (CMOW), which embeds each word as a matrix and uses matrix multiplication to encode sequences. We extend the CMOW architecture and its CMOW/CBOW-Hybrid variant with a bidirectional component for more expressive power, per-token representations for a general (task-agnostic) distillation during pretraining, and a two-sequence encoding scheme that facilitates downstream tasks on sentence pairs, such as sentence similarity and natural language inference. Our matrix-based bidirectional CMOW/CBOW-Hybrid model is competitive to DistilBERT on question similarity and recognizing textual entailment, but uses only half of the number of parameters and is three times faster in terms of inference speed. We match or exceed the scores of ELMo for all tasks of the GLUE benchmark except for the sentiment analysis task SST-2 and the linguistic acceptability task CoLA. However, compared to previous cross-architecture distillation approaches, we demonstrate a doubling of the scores on detecting linguistic acceptability. This shows that matrix-based embeddings can be used to distill large PreLM into competitive models and motivates further research in this direction.

Abstract

Most people have a right-ear advantage for the perception of spoken syllables, consistent with left hemisphere dominance for speech processing. However, there is considerable variation, with some people showing left-ear advantage. The extent to which this variation is reflected in brain structure remains unclear. We tested for relations between hemispheric asymmetries of auditory processing and of grey matter in 281 adults, using dichotic listening and voxel-based morphometry. This was the largest study of this issue to date. Per-voxel asymmetry indexes were derived for each participant following registration of brain magnetic resonance images to a template that was symmetrized. The asymmetry index derived from dichotic listening was related to grey matter asymmetry in clusters of voxels corresponding to the amygdala and cerebellum lobule VI. There was also a smaller, non-significant cluster in the posterior superior temporal gyrus, a region of auditory cortex. These findings contribute to the mapping of asymmetrical structure–function links in the human brain and suggest that subcortical structures should be investigated in relation to hemispheric dominance for speech processing, in addition to auditory cortex.

Abstract

Abstract Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Abstract

The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p‐hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left–right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta‐analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an “ideal publishing environment,” that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically‐used sample sizes.

Abstract

Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last four years, the ENIGMA-Laterality Working Group has published six studies of grey matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an
intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA’s multidataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for grey matter asymmetry based on large, international,
samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders:Autism Spectrum Disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; Pediatric Obsessive-Compulsive Disorder was associated with altered subcortical asymmetry; Major Depressive Disorder was not significantly associated with changes
of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.

Abstract

Executive functioning (EF) plays a major role in many domains of human behaviour, including self-regulation, academic achievement, and even sports expertise. While a significant proportion of cross-sectional research has focused on the developmental pathways of EF, the existing literature is fractionated due to a wide range of methodologies applied to narrow age ranges, impeding comparison across a broad range of age groups. The current study used a cross-sectional design to investigate the factor structure of EF within late childhood and adolescence. A total of 2166 Flemish children and adolescents completed seven tasks of the Cambridge Brain Sciences test battery. Based on the existing literature, a Confirmatory Factor Analysis was performed, which indicated that a unitary factor model provides the best fit for the youngest age group (7–12 years). For the adolescents (12–18 years), the factor structure consists of four different components, including working memory, shifting, inhibition and planning. With regard to differences between early (12–15 years) and late (15–18 years) adolescents, working memory, inhibition and planning show higher scores for the late adolescents, while there was no difference on shifting. The current study is one of the first to administer the same seven EF tests in a considerably large sample of children and adolescents, and as such contributes to the understanding of the developmental trends in EF. Future studies, especially with longitudinal designs, are encouraged to further increase the knowledge concerning the factor structure of EF, and the development of the different EF components.

Abstract

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. The cortical differences we report here could limit the success of treatment of ACHM in adulthood. Interventions earlier in life when cortical structure is not different from normal would likely offer better visual outcomes for those with ACHM.

Abstract

Using individual differences approaches, a growing body of literature finds positive associations between musicality and language-related abilities, complementing prior findings of links between musical training and language skills. Despite these associations, musicality has been often overlooked in mainstream models of individual differences in language acquisition and development. To better understand the biological basis of these individual differences, we propose the Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework. This novel integrative framework posits that musical and language-related abilities likely share some common genetic architecture (i.e., genetic pleiotropy) in addition to some degree of overlapping neural endophenotypes, and genetic influences on musically and linguistically enriched environments. Drawing upon recent advances in genomic methodologies for unraveling pleiotropy, we outline testable predictions for future research on language development and how its underlying neurobiological substrates may be supported by genetic pleiotropy with musicality. In support of the MAPLE framework, we review and discuss findings from over seventy behavioral and neural studies, highlighting that musicality is robustly associated with individual differences in a range of speech-language skills required for communication and development. These include speech perception-in-noise, prosodic perception, morphosyntactic skills, phonological skills, reading skills, and aspects of second/foreign language learning. Overall, the current work provides a clear agenda and framework for studying musicality-language links using individual differences approaches, with an emphasis on leveraging advances in the genomics of complex musicality and language traits.

Abstract

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Abstract

Moving in synchrony to the beat is a fundamental component of musicality. Here we conducted a genome-wide association study to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with 69 loci reaching genome-wide significance (P < 5 × 10−8) and single-nucleotide-polymorphism-based heritability (on the liability scale) of 13%–16%. Heritability was enriched for genes expressed in brain tissues and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central-nervous-system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through separate experiments) and of the genome-wide association study (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations.

Abstract

Temporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated.

Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 TLE patients and 53 healthy controls, and examined clinical associations using machine learning.

We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables.

Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

Abstract

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

Abstract

Learning is using past experiences to inform new behaviors and actions. Because all experiences are unique, learning always requires some generalization. An effective way of improving generalization is to expose learners to more variable (and thus often more representative) input. More variability tends to make initial learning more challenging, but eventually leads to more general and robust performance. This core principle has been repeatedly rediscovered and renamed in different domains (e.g., contextual diversity, desirable difficulties, variability of practice). Reviewing this basic result as it has been formulated in different domains allows us to identify key patterns, distinguish between different kinds of variability, discuss the roles of varying task-relevant versus irrelevant dimensions, and examine the effects of introducing variability at different points in training.

Abstract

On the surface, the fields of animal communication and human linguistics have arrived at conflicting theories and conclusions with respect to the effect of social complexity on communicative complexity. For example, an increase in group size is argued to have opposite consequences on human versus animal communication systems: although an increase in human community size leads to some types of language simplification, an increase in animal group size leads to an increase in signal complexity. But do human and animal communication systems really show such a fundamental discrepancy? Our key message is that the tension between these two adjacent fields is the result of (a) a focus on different levels of analysis (namely, signal variation or grammar-like rules) and (b) an inconsistent use of terminology (namely, the terms “simple” and “complex”). By disentangling and clarifying these terms with respect to different measures of communicative complexity, we show that although animal and human communication systems indeed show some contradictory effects with respect to signal variability, they actually display essentially the same patterns with respect to grammar-like structure. This is despite the fact that the definitions of complexity and simplicity are actually aligned for signal variability, but diverge for grammatical structure. We conclude by advocating for the use of more objective and descriptive terms instead of terms such as “complexity,” which can be applied uniformly for human and animal communication systems—leading to comparable descriptions of findings across species and promoting a more productive dialogue between fields.

Abstract

Many mental health conditions present a spectrum of social difficulties that overlaps with social behaviour in the general population including shared but little characterised genetic links. Here, we systematically investigate heterogeneity in shared genetic liabilities with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BP), major depression (MD) and schizophrenia across a spectrum of different social symptoms. Longitudinally assessed low-prosociality and peer-problem scores in two UK population-based cohorts (4–17 years; parent- and teacher-reports; Avon Longitudinal Study of Parents and Children(ALSPAC): N ≤ 6,174; Twins Early Development Study(TEDS): N ≤ 7,112) were regressed on polygenic risk scores for disorder, as informed by genome-wide summary statistics from large consortia, using negative binomial regression models. Across ALSPAC and TEDS, we replicated univariate polygenic associations between social behaviour and risk for ADHD, MD and schizophrenia. Modelling variation in univariate genetic effects jointly using random-effect meta-regression revealed evidence for polygenic links between social behaviour and ADHD, ASD, MD, and schizophrenia risk, but not BP. Differences in age, reporter and social trait captured 45–88% in univariate effect variation. Cross-disorder adjusted analyses demonstrated that age-related heterogeneity in univariate effects is shared across mental health conditions, while reporter- and social trait-specific heterogeneity captures disorder-specific profiles. In particular, ADHD, MD, and ASD polygenic risk were more strongly linked to peer problems than low prosociality, while schizophrenia was associated with low prosociality only. The identified association profiles suggest differences in the social genetic architecture across mental disorders when investigating polygenic overlap with population-based social symptoms spanning 13 years of child and adolescent development.

Abstract

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

Abstract

The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q‐ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest‐ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi‐site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene‐dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype‐first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

Abstract

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10−10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = −0.40), educational attainment (years of schooling rg = −0.46) and reproductive traits (age at first birth rg = −0.58, father’s age at death rg = −0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

Abstract

When experienced in-person, engagement with art has been associated—in a growing body of evidence—with positive outcomes in wellbeing and mental health. This represents an exciting new field for psychology, curation, and health interventions, suggesting a widely-accessible, cost-effective, and non-pharmaceutical means of regulating factors such as mood or anxiety. However, can similar impacts be found with online presentations? If so, this would open up positive outcomes to an even-wider population—a trend accelerating due to the current COVID-19 pandemic. Despite its promise, this question, and the underlying mechanisms of art interventions and impacts, has largely not been explored. Participants (N = 84) were asked to engage with one of two online exhibitions from Google Arts and Culture (a Monet painting or a similarly-formatted display of Japanese culinary traditions). With just 1–2 min exposure, both improved negative mood, state-anxiety, loneliness, and wellbeing. Stepdown analysis suggested the changes can be explained primarily via negative mood, while improvements in mood correlated with aesthetic appraisals and cognitive-emotional experience of the exhibition. However, no difference was found between exhibitions. We discuss the findings in terms of applications and targets for future research.

Abstract

We address the problem of recommending relevant items to a user in order to "complete" a partial set of items already known. We consider the two scenarios of citation and subject label recommendation, which resemble different semantics of item co-occurrence: relatedness for co-citations and diversity for subject labels. We assess the influence of the completeness of an already known partial item set on the recommender performance. We also investigate data sparsity through a pruning parameter and the influence of using additional metadata. As recommender models, we focus on different autoencoders, which are particularly suited for reconstructing missing items in a set. We extend autoencoders to exploit a multi-modal input of text and structured data. Our experiments on six real-world datasets show that supplying the partial item set as input is helpful when item co-occurrence resembles relatedness, while metadata are effective when co-occurrence implies diversity. This outcome means that the semantics of item co-occurrence is an important factor. The simple item co-occurrence model is a strong baseline for citation recommendation. However, autoencoders have the advantage to enable exploiting additional metadata besides the partial item set as input and achieve comparable performance. For the subject label recommendation task, the title is the most important attribute. Adding more input modalities sometimes even harms the result. In conclusion, it is crucial to consider the semantics of the item co-occurrence for the choice of an appropriate recommendation model and carefully decide which metadata to exploit.

Abstract

Purpose

Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.
Methods

We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.
Results

Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted.
Conclusion

Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.

Abstract

Abstract Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Abstract

Background

Head circumference is associated with intelligence and tracks from childhood into adulthood.
Methods

We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30 months of age.
Results

Seven loci reached genome-wide significance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel. We observed positive genetic correlations for early-life head circumference with adult intracranial volume, years of schooling, childhood and adult intelligence, but not with adult psychiatric, neurological, or personality-related phenotypes.
Conclusions

The results of this study indicate that the biological processes underlying early-life head circumference overlap largely with those of adult head circumference. The associations of early-life head circumference with cognitive outcomes across the life course are partly explained by genetics.

Abstract

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta‐Analysis) Consortium presents the largest‐ever mega‐analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1‐90 years old (47% females). We observed significant patterns of greater male than female between‐subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene‐environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex‐specific vulnerability to disorders.

Abstract

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late
life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438
adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were
also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height.
We found a high genetic correlation with child head circumference (genetic = 0.748), which indicates a similar genetic
background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial
volume were also related to childhood and adult cognitive function, and Parkinson’s disease, and were enriched near genes
involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial
volume and provide genetic support for theories on brain reserve and brain overgrowth.

Abstract

Do individuals differ in how efficiently they process non-native sounds? To what extent do these differences relate to individual variability in sound-learning aptitude? We addressed these questions by assessing the sound-learning abilities of Dutch native speakers as they were trained on non-native tone contrasts. We used fMRI repetition suppression to the non-native tones to measure participants' neuronal processing efficiency before and after training. Although all participants improved in tone identification with training, there was large individual variability in learning performance. A repetition suppression effect to tone was found in the bilateral inferior frontal gyri (IFGs) before training. No whole-brain effect was found after training; a region-of-interest analysis, however, showed that, after training, repetition suppression to tone in the left IFG correlated positively with learning. That is, individuals who were better in learning the non-native tones showed larger repetition suppression in this area. Crucially, this was true even before training. These findings add to existing evidence that the left IFG plays an important role in sound learning and indicate that individual differences in learning aptitude stem from differences in the neuronal efficiency with which non-native sounds are processed.

Abstract

Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype–phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations.

Abstract

Recent genome wide association scans (GWAS) for reading and language abilities have pin-pointed promising new candidate loci. However, the potential contributions of these loci remain to be validated. In the present study, we tested 17 of the most significantly associated single nucleotide polymorphisms (SNPs) from these GWAS studies (p < 10−6 in the original studies) in a new independent population dataset from the Netherlands: known as FIOLA (Familial Influences On Literacy Abilities). This dataset comprised 483 children from 307 nuclear families, plus 505 adults (including parents of participating children), and provided adequate statistical power to detect the effects that were previously reported. The following measures of reading and language performance were collected: word reading fluency, nonword reading fluency, phonological awareness, and rapid automatized naming. Two SNPs (rs12636438, rs7187223) were associated with performance in multivariate and univariate testing, but these did not remain significant after correction for multiple testing. Another SNP (rs482700) was only nominally associated in the multivariate test. For the rest of the SNPs we did not find supportive evidence of association. The findings may reflect differences between our study and the previous investigations in respects such as the language of testing, the exact tests used, and the recruitment criteria. Alternatively, most of the prior reported associations may have been false positives. A larger scale GWAS meta-analysis than those previously performed will likely be required to obtain robust insights into the genomic architecture underlying reading and language.

Abstract

Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here we performed a systematic study of ultrasonic vocalizations (USVs) of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans.

Abstract

A response to Moving Beyond Nature-Nurture: a Problem of Science or Communication? by John Spencer, Mark Blumberg and David Shenk

Abstract

Recently, there has been an explosion in the availability of large, good-quality cross-linguistic databases such as WALS (Dryer & Haspelmath, 2013), Glottolog (Hammarstrom et al., 2015) and Phoible (Moran & McCloy, 2014). Databases such as Phoible contain the actual segments used by various languages as they are given in the primary language descriptions. However, this segment-level representation cannot be used directly for analyses that require generalizations over classes of segments that share theoretically interesting features. Here we present a method and the associated R (R Core Team, 2014) code that allows the exible denition of such meaningful classes and that can identify the sets of segments falling into such a class for any language inventory. The method and its results are important for those interested in exploring cross-linguistic patterns of phonetic and phonological diversity and their relationship to extra-linguistic factors and processes such as climate, economics, history or human genetics.

Abstract

The current paper presents results for data on click learning obtained from a larger imaging study (using MRI and 3D intraoral scanning) designed to quantify and characterize intra- and inter-population variation of vocal tract structures and the relation of this to speech production. The aim of the click study was to ascertain whether and to what extent vocal tract morphology influences (1) the ability to learn to produce clicks and (2) the productions of those that successfully learn to produce these sounds. The results indicate that the presence of an alveolar ridge certainly does not prevent an individual from learning to produce click sounds (1). However, the subtle details of how clicks are produced may indeed be driven by palate shape (2).

Abstract

Interest in the origins and evolution of language has been around for as long as language has been around. However, only recently has the empirical study of language come of age. We argue that the field has sufficiently advanced that it now needs its own journal—the Journal of Language Evolution.

Abstract

Our understanding of language, its origins and subsequent evolution (including language change) is shaped not only by data and theories from the language sciences, but also fundamentally by the biological sciences. Recent developments in genetics and evolutionary theory offer both very strong constraints on what scenarios of language evolution are possible and probable but also offer exciting opportunities for understanding otherwise puzzling phenomena. Due to the intrinsic breathtaking rate of advancement in these fields, the complexity, subtlety and sometimes apparent non-intuitiveness of the phenomena discovered, some of these recent developments have either being completely missed by language scientists, or misperceived and misrepresented. In this short paper, we offer an update on some of these findings and theoretical developments through a selection of illustrative examples and discussions that cast new light on current debates in the language sciences. The main message of our paper is that life is much more complex and nuanced than anybody could have predicted even a few decades ago, and that we need to be flexible in our theorizing instead of embracing a priori dogmas and trying to patch paradigms that are no longer satisfactory.

Abstract

Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes

Abstract

Adherence to medications is an important indicator of the quality of medication management and impacts on health outcomes and cost-effectiveness of healthcare delivery. Electronic healthcare data (EHD) are increasingly used to estimate adherence in research and clinical practice, yet standardization and transparency of data processing are still a concern. Comprehensive and flexible open-source algorithms can facilitate the development of high-quality, consistent, and reproducible evidence in this field. Some EHD-based clinical decision support systems (CDSS) include visualization of medication histories, but this is rarely integrated in adherence analyses and not easily accessible for data exploration or implementation in new clinical settings. We introduce AdhereR, a package for the widely used open-source statistical environment R, designed to support researchers in computing EHD-based adherence estimates and in visualizing individual medication histories and adherence patterns. AdhereR implements a set of functions that are consistent with current adherence guidelines, definitions and operationalizations. We illustrate the use of AdhereR with an example dataset of 2-year records of 100 patients and describe the various analysis choices possible and how they can be adapted to different health conditions and types of medications. The package is freely available for use and its implementation facilitates the integration of medication history visualizations in open-source CDSS platforms.

Abstract

Mutations affecting the transcription factor FOXP2 cause a rare form of severe speech and language disorder. Although it is clear that sufficient FOXP2 expression is crucial for normal brain development, little is known about how this transcription factor is regulated. To investigate post-translational mechanisms for FOXP2 regulation, we searched for protein interaction partners of FOXP2, and identified members of the PIAS family as novel FOXP2 interactors. PIAS proteins mediate post-translational modification of a range of target proteins with small ubiquitin-like modifiers (SUMOs). We found that FOXP2 can be modified with all three human SUMO proteins and that PIAS1 promotes this process. An aetiological FOXP2 mutation found in a family with speech and language disorder markedly reduced FOXP2 SUMOylation. We demonstrate that FOXP2 is SUMOylated at a single major site, which is conserved in all FOXP2 vertebrate orthologues and in the paralogues FOXP1 and FOXP4. Abolishing this site did not lead to detectable changes in FOXP2 subcellular localization, stability, dimerization or transcriptional repression in cellular assays, but the conservation of this site suggests a potential role for SUMOylation in regulating FOXP2 activity in vivo.

Abstract

Childhood adversity (CA) has been associated with long-term structural brain alterations and an increased risk for psychiatric disorders. Evidence is emerging that subtypes of CA, varying in the dimensions of threat and deprivation, lead to distinct neural and behavioral outcomes. However, these specific associations have yet to be established without potential confounders such as psychopathology. Moreover, differences in neural development and psychopathology necessitate the exploration of sexual dimorphism. Young healthy adult subjects were selected based on history of CA from a large database to assess gray matter (GM) differences associated with specific subtypes of adversity. We compared voxel-based morphometry data of subjects reporting specific childhood exposure to abuse (n = 127) or deprivation (n = 126) and a similar sized group of controls (n = 129) without reported CA. Subjects were matched on age, gender, and educational level. Differences between CA subtypes were found in the fusiform gyrus and middle occipital gyms, where subjects with a history of deprivation showed reduced GM compared with subjects with a history of abuse. An interaction between sex and CA subtype was found. Women showed less GM in the visual posterior precuneal region after both subtypes of CA than controls. Men had less GM in the postcentral gyms after childhood deprivation compared with abuse. Our results suggest that even in a healthy population, CA subtypes are related to specific alterations in brain structure, which are modulated by sex. These findings may help understand neurodevelopmental consequences related to CA

Abstract

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Abstract

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia

Abstract

Individuals with heterozygous 16p11.2 deletions reportedly suffer from a variety of difficulties with speech and language. Indeed, recent copy-number variant screens of children with childhood apraxia of speech (CAS), a specific and rare motor speech disorder, have identified three unrelated individuals with 16p11.2 deletions. However, the nature and prevalence of speech and language disorders in general, and CAS in particular, is unknown for individuals with 16p11.2 deletions. Here we took a genotype-first approach, conducting detailed and systematic characterization of speech abilities in a group of 11 unrelated children ascertained on the basis of 16p11.2 deletions. To obtain the most precise and replicable phenotyping, we included tasks that are highly diagnostic for CAS, and we tested children under the age of 18 years, an age group where CAS has been best characterized. Two individuals were largely nonverbal, preventing detailed speech analysis, whereas the remaining nine met the standard accepted diagnostic criteria for CAS. These results link 16p11.2 deletions to a highly penetrant form of CAS. Our findings underline the need for further precise characterization of speech and language profiles in larger groups of affected individuals, which will also enhance our understanding of how genetic pathways contribute to human communication disorders.

Abstract

The rise of genomic technologies has yielded exciting new routes for studying the biological foundations of language. Researchers have begun to identify genes implicated in neurodevelopmental disorders that disrupt speech and language skills. This chapter illustrates how such work can provide powerful entry points into the critical neural pathways using FOXP2 as an example. Rare mutations of this gene cause problems with learning to sequence mouth movements during speech, accompanied by wide-ranging impairments in language production and comprehension. FOXP2 encodes a regulatory protein, a hub in a network of other genes, several of which have also been associated with language-related impairments. Versions of FOXP2 are found in similar form in many vertebrate species; indeed, studies of animals and birds suggest conserved roles in the development and plasticity of certain sets of neural circuits. Thus, the contributions of this gene to human speech and language involve modifications of evolutionarily ancient functions.

Abstract

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders

Abstract

Adult mouse ultrasonic vocalizations (USVs) occur in multiple behavioral and stimulus contexts associated with various levels of arousal, emotion, and social interaction. Here, in three experiments of increasing stimulus intensity (water; female urine; male interacting with adult female), we tested the hypothesis that USVs of adult males express the strength of arousal and emotion via different USV parameters (18 parameters analyzed). Furthermore, we analyzed two mouse lines with heterozygous Foxp2 mutations (R552H missense, S321X nonsense), known to produce severe speech and language disorders in humans. These experiments allowed us to test whether intact Foxp2 function is necessary for developing full adult USV repertoires, and whether mutations of this gene influence instinctive vocal expressions based on arousal and emotion. The results suggest that USV calling rate characterizes the arousal level, while sound pressure and spectro-temporal call complexity (overtones/harmonics, type of frequency jumps) may provide indices of levels of positive emotion. The presence of Foxp2 mutations did not qualitatively affect the USVs; all USV types that were found in wild-type animals also occurred in heterozygous mutants. However, mice with Foxp2 mutations displayed quantitative differences in USVs as compared to wild-types, and these changes were context dependent. Compared to wild-type animals, heterozygous mutants emitted mainly longer and louder USVs at higher minimum frequencies with a higher occurrence rate of overtones/harmonics and complex frequency jump types. We discuss possible hypotheses about Foxp2 influence on emotional vocal expressions, which can be investigated in future experiments using selective knockdown of Foxp2 in specific brain circuits.

Abstract

Background

Reading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs).
Methods

In a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV−), and we analyzed continuous probe intensity data using FamCNV.
Results

No significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10−2–10−3) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026–0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10−2–10−4) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls.
Conclusions

These data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.

Abstract

We examined whether assortative mating for educational attainment (“like marries like”) can be detected in the genomes of ~ 1600 UK spouse pairs of European descent. Assortative mating on heritable traits like educational attainment increases the genetic variance and heritability of the trait in the population, which may increase social inequalities. We test for genetic assortative mating in the UK on educational attainment, a phenotype that is indicative of socio-economic status and has shown substantial levels of assortative mating. We use genome-wide allelic effect sizes from a large genome-wide association study on educational attainment (N ~ 300 k) to create polygenic scores that are predictive of educational attainment in our independent sample (r = 0.23, p < 2 × 10− 16). The polygenic scores significantly predict partners' educational outcome (r = 0.14, p = 4 × 10− 8 and r = 0.19, p = 2 × 10− 14, for prediction from males to females and vice versa, respectively), and are themselves significantly correlated between spouses (r = 0.11, p = 7 × 10− 6). Our findings provide molecular genetic evidence for genetic assortative mating on education in the UK

Abstract

Coevolving systems are notoriously difficult to understand. This is largely due to the Red Queen effect that dictates heterospecific fitness interdependence. In simulation studies of coevolving systems, master tournaments are often used to obtain more informed fitness measures by testing evolved individuals against past and future opponents. However, such tournaments still contain certain ambiguities. We introduce the use of a phenotypic cluster analysis to examine the distribution of opponent categories throughout an evolutionary sequence. This analysis, adopted from widespread usage in the bioinformatics community, can be applied to master tournament data. This allows us to construct behavior-based category trees, obtaining a hierarchical classification of phenotypes that are suspected to interleave during cyclic evolution. We use the cluster data to establish the existence of switching-genes that control opponent specialization, suggesting the retention of dormant genetic adaptations, that is, genetic memory. Our overarching goal is to reiterate how computer simulations may have importance to the broader understanding of evolutionary dynamics in general. We emphasize a further shift from a component-driven to an interaction-driven perspective in understanding coevolving systems. As yet, it is unclear how the sudden development of switching-genes relates to the gradual emergence of genetic adaptability. Likely, context genes gradually provide the appropriate genetic environment wherein the switching-gene effect can be exploited

Abstract

In Iterated Learning (IL) experiments, a participant’s learned output serves as the next participant’s learning input (Kirby et al., 2014). IL can be used to model cultural transmission and has indicated that weak biases can be amplified through repeated cultural transmission (Kirby et al., 2007). So, for example, structural language properties can emerge over time because languages come to reflect the cognitive constraints in the individuals that learn and produce the language. Similarly, we propose that languages may also reflect certain anatomical biases. Do sound systems adapt to the affordances of the articulation space induced by the vocal tract?
The human vocal tract has inherent nonlinearities which might derive from acoustics and aerodynamics (cf. quantal theory, see Stevens, 1989) or biomechanics (cf. Gick & Moisik, 2015). For instance, moving the tongue anteriorly along the hard palate to produce a fricative does not result in large changes in acoustics in most cases, but for a small range there is an abrupt change from a perceived palato-alveolar [ʃ] to alveolar [s] sound (Perkell, 2012). Nonlinearities such as these might bias all human speakers to converge on a very limited set of phonetic categories, and might even be a basis for combinatoriality or phonemic ‘universals’.
While IL typically uses discrete symbols, Verhoef et al. (2014) have used slide whistles to produce a continuous signal. We conducted an IL experiment with human subjects who communicated using a digital slide whistle for which the degree of nonlinearity is controlled. A single parameter (α) changes the mapping from slide whistle position (the ‘articulator’) to the acoustics. With α=0, the position of the slide whistle maps Bark-linearly to the acoustics. As α approaches 1, the mapping gets more double-sigmoidal, creating three plateaus where large ranges of positions map to similar frequencies. In more abstract terms, α represents the strength of a nonlinear (anatomical) bias in the vocal tract.
Six chains (138 participants) of dyads were tested, each chain with a different, fixed α. Participants had to communicate four meanings by producing a continuous signal using the slide-whistle in a ‘director-matcher’ game, alternating roles (cf. Garrod et al., 2007).
Results show that for high αs, subjects quickly converged on the plateaus. This quick convergence is indicative of a strong bias, repelling subjects away from unstable regions already within-subject. Furthermore, high αs lead to the emergence of signals that oscillate between two (out of three) plateaus. Because the sigmoidal spaces are spatially constrained, participants increasingly used the sequential/temporal dimension. As a result of this, the average duration of signals with high α was ~100ms longer than with low α. These oscillations could be an expression of a basis for phonemic combinatoriality.
We have shown that it is possible to manipulate the magnitude of an articulator-induced non-linear bias in a slide whistle IL framework. The results suggest that anatomical biases might indeed constrain the design space of language. In particular, the signaling systems in our study quickly converged (within-subject) on the use of stable regions. While these conclusions were drawn from experiments using slide whistles with a relatively strong bias, weaker biases could possibly be amplified over time by repeated cultural transmission, and likely lead to similar outcomes.

Abstract

Many factors have been proposed to explain why groups of people use different speech sounds in their language. These range from cultural, cognitive, environmental (e.g., Everett, et al., 2015) to anatomical (e.g., vocal tract (VT) morphology). How could such anatomical properties have led to the similarities and differences in speech sound distributions between human languages?

It is known that hard palate profile variation can induce different articulatory strategies in speakers (e.g., Brunner et al., 2009). That is, different hard palate profiles might induce a kind of bias on speech sound production, easing some types of sounds while impeding others. With a population of speakers (with a proportion of individuals) that share certain anatomical properties, even subtle VT biases might become expressed at a population-level (through e.g., bias amplification, Kirby et al., 2007). However, before we look into population-level effects, we should first look at within-individual anatomical factors. For that, we have developed a computer-simulated analogue for a human speaker: an agent. Our agent is designed to replicate speech sounds using a production and cognition module in a computationally tractable manner.

Previous agent models have often used more abstract (e.g., symbolic) signals. (e.g., Kirby et al., 2007). We have equipped our agent with a three-dimensional model of the VT (the production module, based on Birkholz, 2005) to which we made numerous adjustments. Specifically, we used a 4th-order Bezier curve that is able to capture hard palate variation on the mid-sagittal plane (XXX, 2015). Using an evolutionary algorithm, we were able to fit the model to human hard palate MRI tracings, yielding high accuracy fits and using as little as two parameters. Finally, we show that the samples map well-dispersed to the parameter-space, demonstrating that the model cannot generate unrealistic profiles. We can thus use this procedure to import palate measurements into our agent’s production module to investigate the effects on acoustics. We can also exaggerate/introduce novel biases.

Our agent is able to control the VT model using the cognition module.

Previous research has focused on detailed neurocomputation (e.g., Kröger et al., 2014) that highlights e.g., neurobiological principles or speech recognition performance. However, the brain is not the focus of our current study. Furthermore, present-day computing throughput likely does not allow for large-scale deployment of these architectures, as required by the population model we are developing. Thus, the question whether a very simple cognition module is able to replicate sounds in a computationally tractable manner, and even generalize over novel stimuli, is one worthy of attention in its own right.

Our agent’s cognition module is based on running an evolutionary algorithm on a large population of feed-forward neural networks (NNs). As such, (anatomical) bias strength can be thought of as an attractor basin area within the parameter-space the agent has to explore. The NN we used consists of a triple-layered (fully-connected), directed graph. The input layer (three neurons) receives the formants frequencies of a target-sound. The output layer (12 neurons) projects to the articulators in the production module. A hidden layer (seven neurons) enables the network to deal with nonlinear dependencies. The Euclidean distance (first three formants) between target and replication is used as fitness measure. Results show that sound replication is indeed possible, with Euclidean distance quickly approaching a close-to-zero asymptote.

Statistical analysis should reveal if the agent can also: a) Generalize: Can it replicate sounds not exposed to during learning? b) Replicate consistently: Do different, isolated agents always converge on the same sounds? c) Deal with consolidation: Can it still learn new sounds after an extended learning phase (‘infancy’) has been terminated? Finally, a comparison with more complex models will be used to demonstrate robustness.

Abstract

Pinpointing genes involved in non-right-handedness has the potential to clarify developmental contributions to human brain lateralization. Major-gene models have been considered for human handedness which allow for phenocopy and reduced penetrance, i.e. an imperfect correspondence between genotype and phenotype. However, a recent genome-wide association scan did not detect any common polymorphisms with substantial genetic effects. Previous linkage studies in families have also not yielded significant findings. Genetic heterogeneity and/or polygenicity are therefore indicated, but it remains possible that relatively rare, or even unique, major-genetic effects may be detectable in certain extended families with many non-right-handed members. Here we applied whole exome sequencing to 17 members from a single, large consanguineous family from Pakistan. Multipoint linkage analysis across all autosomes did not yield clear candidate genomic regions for involvement in the trait and single-point analysis of exomic variation did not yield clear candidate mutations/genes. Any genetic contribution to handedness in this unusual family is therefore likely to have a complex etiology, as at the population level.

Abstract

A steady accumulation of experimental data argues that protein synthesis in neurons is not merely restricted to the somatic compartment, but also occurs in several discrete cellular micro-domains. Local protein synthesis is critical for the establishment of synaptic plasticity in mature dendrites and in directing the growth cones of immature axons, and has been associated with cognitive impairment in mice and humans. Although in recent years a number of important mechanisms governing this process have been described, it remains technically challenging to precisely monitor local protein synthesis in individual neuronal cell parts independent from the soma. This report presents the utility of employing microfluidic chambers for the isolation and treatment of single neuronal cellular compartments. Furthermore, it is demonstrated that a protein synthesis assay, based on fluorescent non-canonical amino acid tagging (FUNCAT), can be combined with this cell culture system to label nascent proteins within a discrete structural and functional domain of the neuron. Together, these techniques could be employed for the detection of protein synthesis within developing and mature neurites, offering an effective approach to elucidate novel mechanisms controlling synaptic maintenance and plasticity.

Abstract

Objective To elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. Method Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (< 13 years) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. Results SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46×10-6 and 2.66×10-6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. Conclusion The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and improve statistical power for identifying genetic variants.

Abstract

The inhibitory mechanisms that prevent gene expression programs from one tissue to be expressed in another are poorly understood. Foxp1/2/4 are forkhead transcription factors that repress gene expression and are individually important for endoderm development. We show that combined loss of all three Foxp1/2/4 family members in the developing anterior foregut endoderm leads to a loss of lung endoderm lineage commitment and subsequent development. Foxp1/2/4 deficient lungs express high levels of transcriptional regulators not normally expressed in the developing lung, including Pax2, Pax8, Pax9 and the Hoxa9-13 cluster. Ectopic expression of these transcriptional regulators is accompanied by decreased expression of lung restricted transcription factors including Nkx2-1, Sox2, and Sox9. Foxp1 binds to conserved forkhead DNA binding sites within the Hoxa9-13 cluster, indicating a direct repression mechanism. Thus, Foxp1/2/4 are essential for promoting lung endoderm development by repressing expression of non-pulmonary transcription factors

Abstract

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

Abstract

Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an animal model displaying schizophrenia-relevant features, the apomorphine-susceptible (APO-SUS) rat and its phenotypic counterpart, the apomorphine-unsusceptible (APO-UNSUS) rat at postnatal day 20-22. We found changes in the expression of the GABA-synthesizing enzyme GAD67 specifically in the prelimbic-but not the infralimbic region of the medial prefrontal cortex (mPFC), indicative of reduced inhibitory function in this region in APO-SUS rats. While we did not observe changes in basal synaptic transmission onto LII/III pyramidal cells in the mPFC of APO-SUS compared to APO-UNSUS rats, we report reduced paired-pulse ratios at longer inter-stimulus intervals. The GABA(B) receptor antagonist CGP 55845 abolished this reduction, indicating that the decreased paired-pulse ratio was caused by increased GABA(B) signaling. Consistently, we find an increased expression of the GABA(B1) receptor subunit in APO-SUS rats. Our data provide physiological evidence for increased presynaptic GABAB signaling in the mPFC of APO-SUS rats, further supporting an important role for the GABAergic system in the pathophysiology of schizophrenia.

Abstract

De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

Abstract

s Metrics Comments Related Content Abstract Introduction Materials and Methods Results Discussion Supporting Information Acknowledgments Author Contributions References Reader Comments (0) Media Coverage Figures Abstract Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.