Publications

Abstract

Linguistic diversity, now and in the past, is widely regarded to be independent of biological changes that took place after the emergence of Homo sapiens. We show converging evidence from paleoanthropology, speech biomechanics, ethnography, and historical linguistics that labiodental sounds (such as “f” and “v”) were innovated after the Neolithic. Changes in diet attributable to food-processing technologies modified the human bite from an edge-to-edge configuration to one that preserves adolescent overbite and overjet into adulthood. This change favored the emergence and maintenance of labiodentals. Our findings suggest that language is shaped not only by the contingencies of its history, but also by culturally induced changes in human biology.

Abstract

Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.

Abstract

FOXP proteins form a subfamily of evolutionarily conserved transcription factors involved in the development and functioning of several tissues, including the central nervous system. In humans, mutations in FOXP1 and FOXP2 have been implicated in cognitive deficits including intellectual disability and speech disorders. Drosophila exhibits a single ortholog, called FoxP, but due to a lack of characterized mutants, our understanding of the gene remains poor. Here we show that the dimerization property required for mammalian FOXP function is conserved in Drosophila. In flies, FoxP is enriched in the adult brain, showing strong expression in ~1000 neurons of cholinergic, glutamatergic and GABAergic nature. We generate Drosophila loss-of-function mutants and UAS-FoxP transgenic lines for ectopic expression, and use them to characterize FoxP function in the nervous system. At the cellular level, we demonstrate that Drosophila FoxP is required in larvae for synaptic morphogenesis at axonal terminals of the neuromuscular junction and for dendrite development of dorsal multidendritic sensory neurons. In the developing brain, we find that FoxP plays important roles in α-lobe mushroom body formation. Finally, at a behavioral level, we show that Drosophila FoxP is important for locomotion, habituation learning and social space behavior of adult flies. Our work shows that Drosophila FoxP is important for regulating several neurodevelopmental processes and behaviors that are related to human disease or vertebrate disease model phenotypes. This suggests a high degree of functional conservation with vertebrate FOXP orthologues and established flies as a model system for understanding FOXP related pathologies.

Abstract

This paper argues that inter-individual and inter-group variation in language acquisition, perception, processing and production, rooted in our biology, may play a largely neglected role in sound change. We begin by discussing the patterning of these differences, highlighting those related to vocal tract anatomy with a foundation in genetics and development. We use our ArtiVarK database, a large multi-ethnic sample comprising 3D intraoral optical scans, as well as structural, static and real-time MRI scans of vocal tract anatomy and speech articulation, to quantify the articulatory strategies used to produce the North American English /r/ and to statistically show that anatomical factors seem to influence these articulatory strategies. Building on work showing that these alternative articulatory strategies may have indirect coarticulatory effects, we propose two models for how biases due to variation in vocal tract anatomy may affect sound change. The first involves direct overt acoustic effects of such biases that are then reinterpreted by the hearers, while the second is based on indirect coarticulatory phenomena generated by acoustically covert biases that produce overt “at-a-distance” acoustic effects. This view implies that speaker communities might be “poised” for change because they always contain pools of “standing variation” of such biased speakers, and when factors such as the frequency of the biased speakers in the community, their positions in the communicative network or the topology of the network itself change, sound change may rapidly follow as a self-reinforcing network-level phenomenon, akin to a phase transition. Thus, inter-speaker variation in structured and dynamic communicative networks may couple the initiation and actuation of sound change.

Abstract

Linguistic diversity is affected by multiple factors, but it is usually assumed that variation in the anatomy of our speech organs
plays no explanatory role. Here we use realistic computer models of the human speech organs to test whether inter-individual
and inter-group variation in the shape of the hard palate (the bony roof of the mouth) affects acoustics of speech sounds. Based
on 107 midsagittal MRI scans of the hard palate of human participants, we modelled with high accuracy the articulation of a set
of five cross-linguistically representative vowels by agents learning to produce speech sounds. We found that different hard
palate shapes result in subtle differences in the acoustics and articulatory strategies of the produced vowels, and that these
individual-level speech idiosyncrasies are amplified by the repeated transmission of language across generations. Therefore,
we suggest that, besides culture and environment, quantitative biological variation can be amplified, also influencing language.

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Abstract

This chapter discusses the genetic foundations of the human capacity for language. It reviews the molecular structure of the genome and the complex molecular mechanisms that allow genetic information to influence multiple levels of biology. It goes on to describe the active regulation of genes and their formation of complex genetic pathways that in turn control the cellular environment and function. At each of these levels, examples of genes and genetic variants that may influence the human capacity for language are given. Finally, it discusses the value of using animal models to understand the genetic underpinnings of speech and language. From this chapter will emerge the complexity of the genome in action and the multidisciplinary efforts that are currently made to bridge the gap between genetics and language.

Abstract

Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

Abstract

FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds no evidence of recent adaptive evolution.

Abstract

Disruptions of the FOXP2 gene cause a speech and language disorder involving difficulties in sequencing orofacial movements. FOXP2 is expressed in cortico-striatal and cortico-cerebellar circuits important for fine motor skills, and affected individuals show abnormalities in these brain regions. We selectively disrupted Foxp2 in the cerebellar Purkinje cells, striatum or cortex of mice and assessed the effects on skilled motor behaviour using an operant lever-pressing task. Foxp2 loss in each region impacted behaviour differently, with striatal and Purkinje cell disruptions affecting the variability and the speed of lever-press sequences, respectively. Mice lacking Foxp2 in Purkinje cells showed a prominent phenotype involving slowed lever pressing as well as deficits in skilled locomotion. In vivo recordings from Purkinje cells uncovered an increased simple spike firing rate and decreased modulation of firing during limb movements. This was caused by increased intrinsic excitability rather than changes in excitatory or inhibitory inputs. Our findings show that Foxp2 can modulate different aspects of motor behaviour in distinct brain regions, and uncover an unknown role for Foxp2 in the modulation of Purkinje cell activity that severely impacts skilled movements.

Abstract

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Abstract

One of the features that distinguishes modern humans from our extinct relatives
and ancestors is a globular shape of the braincase [1-4]. As the endocranium
closely mirrors the outer shape of the brain, these differences might reflect
altered neural architecture [4,5]. However, in the absence of fossil brain tissue the
underlying neuroanatomical changes as well as their genetic bases remain
elusive. To better understand the biological foundations of modern human
endocranial shape, we turn to our closest extinct relatives, the Neandertals.
Interbreeding between modern humans and Neandertals has resulted in
introgressed fragments of Neandertal DNA in the genomes of present-day non-
Africans [6,7]. Based on shape analyses of fossil skull endocasts, we derive a
measure of endocranial globularity from structural magnetic resonance imaging
(MRI) scans of thousands of modern humans, and study the effects of
introgressed fragments of Neandertal DNA on this phenotype. We find that
Neandertal alleles on chromosomes 1 and 18 are associated with reduced
endocranial globularity. These alleles influence expression of two nearby genes,
UBR4 and PHLPP1, which are involved in neurogenesis and myelination,
respectively. Our findings show how integration of fossil skull data with archaic
genomics and neuroimaging can suggest developmental mechanisms that may
contribute to the unique modern human endocranial shape.

Abstract

Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA‐L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico‐limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219–284 across modalities) and network‐based statistics (NBS) to probe the specificity of MAOA‐L‐related connectomic alterations to cortical‐limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA‐L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between‐lobe (“anisocoupled”) network links and showed a pronounced involvement of frontal‐temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting‐state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA‐L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences affecting these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic influences and low-frequency genetic variation. To understand these influences, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Abstract

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual’s self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner’s self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual’s weekly alcohol consumption increases partner’s alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10−6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.

Abstract

Aim: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. Materials & methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. Results & conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.

Abstract

Mirror-sensory synaesthetes mirror the pain or touch that they observe in other people on their own bodies. This type of synaesthesia has been associated with enhanced empathy. We investigated whether the enhanced empathy of people with mirror-sensory synesthesia influences the experience of situations involving touch or pain and whether it affects their prosocial decision making. Mirror-sensory synaesthetes (N = 18, all female), verified with a touch-interference paradigm, were compared with a similar number of age-matched control individuals (all female). Participants viewed arousing images depicting pain or touch; we recorded subjective valence and arousal ratings, and physiological responses, hypothesizing more extreme reactions in synaesthetes. The subjective impact of positive and negative images was stronger in synaesthetes than in control participants; the stronger the reported synaesthesia, the more extreme the picture ratings. However, there was no evidence for differential physiological or hormonal responses to arousing pictures. Prosocial decision making was assessed with an economic game assessing altruism, in which participants had to divide money between themselves and a second player. Mirror-sensory synaesthetes donated more money than non-synaesthetes, showing enhanced prosocial behaviour, and also scored higher on the Interpersonal Reactivity Index as a measure of empathy. Our study demonstrates the subjective impact of mirror-sensory synaesthesia and its stimulating influence on prosocial behaviour.

Abstract

The influence of larynx position on vowel articulation is an important topic in understanding speech production, the present-day distribution of linguistic diversity and the evolution of speech and language in our lineage. We introduce here a realistic computer model of the vocal tract, constructed from actual human MRI data, which can learn, using machine learning techniques, to control the articulators in such a way as to produce speech sounds matching as closely as possible to a given set of target vowels. We systematically control the vertical position of the larynx and we quantify the differences between the target and produced vowels for each such position across multiple replications. We report that, indeed, larynx height does affect the accuracy of reproducing the target vowels and the distinctness of the produced vowel system, that there is a “sweet spot” of larynx positions that are optimal for vowel production, but that nevertheless, even extreme larynx positions do not result in a collapsed or heavily distorted vowel space that would make speech unintelligible. Together with other lines of evidence, our results support the view that the vowel space of human languages is influenced by our larynx position, but that other positions of the larynx may also be fully compatible with speech.

Abstract

Neurons of the neocortex are organized into six radial layers, which have appeared at different times during evolution, with the superficial layers representing a more recent acquisition. Input to the neocortex predominantly reaches superficial layers (SL, i.e., layers (L) 2-4), while output is generated in deep layers (DL, i.e., L5-6) [1]. Intracortical connections, which bridge input and output pathways, are key components of cortical circuits because they allow the propagation and processing of information within the neocortex. Two main types of intracortically projecting neurons (ICPN) can be distinguished by their axonal features: L4 spiny stellate neurons (SSN) with short axons projecting locally within cortical columns [2, 3, 4, 5], and SL and DL long-range projection neurons, including callosally projecting neurons (CPNSL and CPNDL) [5, 6]. Here, we investigate the molecular hallmarks that distinguish SSN, CPNSL, and CPNDL and relate their transcriptional signatures with their output connectivity. Specifically, taking advantage of the presence of CPN in both SL and DL, we identify lamina-independent genetic hallmarks of a constant projection motif (i.e., interhemispheric projection). By performing unbiased transcriptomic comparisons between CPNSL, CPNDL and SSN, we provide specific molecular profiles for each of these populations and show that target identity supersedes laminar position in defining ICPN transcriptional diversity. Together, these findings reveal a projection-based organization of transcriptional programs across cortical layers, which we propose reflects conserved strategy to protect canonical circuit structure (and hence function) across a diverse range of neuroanatomies.

Abstract

Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, hand preference was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference.

Abstract

Objective:

Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.
Methods:

The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen’s d=0.1.
Results:

The largest effect size (Cohen’s d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.
Conclusions:

Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Abstract

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.

Abstract

Schizophrenia is a common and complex mental disorder with neuroimaging alterations. Recent neuroanatomical pattern recognition studies attempted to distinguish individuals with schizophrenia by structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI). 1, 2 Applications of cutting-edge machine learning approaches in structural neuroimaging studies have revealed potential pathways to classification of schizophrenia based on regional gray matter volume (GMV) or density or cortical thickness. 3–5 Additionally, cortical folding may have high discriminatory value in correctly identifying symptom severity in schizophrenia. 6 Regional GMV and cortical thickness have also been combined in attempts to differentiate individuals with schizophrenia from healthy controls (HCs). 7 Applications of machine learning algorithms to diffusion imaging data analysis to predict individuals with first-episode schizophrenia (FES) have achieved encouraging accuracy. 8–10 White matter (WM) abnormalities in schizophrenia as estimated by DTI appear to be present in the early stage of the disorder, most likely reflecting the developmental stage of the sample of interest.

Abstract

Identifying data-driven biotypes of major depressive disorder (MDD) has promise for the clarification of diagnostic heterogeneity. However, few studies have focused on white-matter abnormalities for MDD subtyping. This study included 116 patients with MDD and 118 demographically-matched healthy controls assessed by diffusion tensor imaging and neurocognitive evaluation. Hierarchical clustering was applied to the major fiber tracts, in conjunction with tract-based spatial statistics, to reveal white-matter alterations associated with MDD. Clinical and neurocognitive differences were compared between identified subgroups and healthy controls. With fractional anisotropy extracted from 20 fiber tracts, cluster analysis revealed 3 subgroups based on the patterns of abnormalities. Patients in each subgroup versus healthy controls showed a stepwise pattern of white-matter alterations as follows: subgroup 1 (25.9% of patient sample), widespread white-matter disruption; subgroup 2 (43.1% of patient sample), intermediate and more localized abnormalities in aspects of the corpus callosum and left cingulate; and subgroup 3 (31.0% of patient sample), possible mild alterations, but no statistically significant tract disruption after controlling for family-wise error. The neurocognitive impairment in each subgroup accompanied the white-matter alterations: subgroup 1, deficits in sustained attention and delayed memory; subgroup 2, dysfunction in delayed memory; and subgroup 3, no significant deficits. Three subtypes of white-matter abnormality exist in individuals with major depression, those having widespread abnormalities suffering more neurocognitive impairments, which may provide evidence for parsing the heterogeneity of the disorder and help optimize type-specific treatment approaches.

Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

Abstract

The anterior lordosis of the cervical spine is thought
to contribute to pitch (fo) production by influencing
cricoid rotation as a function of larynx height. This
study examines the matter of inter-individual
variation in cervical spine shape and whether this has
an influence on how fo is produced along increasing
or decreasing scales, using the ArtiVarK dataset,
which contains real-time MRI pitch production data.
We find that the cervical spine actively participates in
fo production, but the amount of displacement
depends on individual shape. In general, anterior
spine motion (tending toward cervical lordosis)
occurs for low fo, while posterior movement (tending
towards cervical kyphosis) occurs for high fo.

Abstract

Objective

Resting-state functional magnetic resonance imaging (fMRI) is promising for Alzheimer’s disease (AD). This study aimed to examine short-term reliability of the default-mode network (DMN), one of the main haemodynamic patterns of the brain.
Materials and methods

Using a 1.5 T Philips Achieva scanner, two consecutive resting-state fMRI runs were acquired on 69 healthy adults, 62 patients with mild cognitive impairment (MCI) due to AD, and 28 patients with AD dementia. The anterior and posterior DMN and, as control, the visual-processing network (VPN) were computed using two different methodologies: connectivity of predetermined seeds (theory-driven) and dual regression (data-driven). Divergence and convergence in network strength and topography were calculated with paired t tests, global correlation coefficients, voxel-based correlation maps, and indices of reliability.
Results

No topographical differences were found in any of the networks. High correlations and reliability were found in the posterior DMN of healthy adults and MCI patients. Lower reliability was found in the anterior DMN and in the VPN, and in the posterior DMN of dementia patients.
Discussion

Strength and topography of the posterior DMN appear relatively stable and reliable over a short-term period of acquisition but with some degree of variability across clinical samples.

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Abstract

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

Abstract

Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme–colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging.

Abstract

Background Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms.

Objective To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach.

Methods We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted.

Results Genome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule.

Conclusion This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

Abstract

A commonly held assumption in cognitive neuroscience is that, because measures of human brain function are closer to underlying biology than distal indices of behavior/cognition, they hold more promise for uncovering genetic pathways. Supporting this view is an influential fMRI-based study of sentence reading/listening by Pinel et al. (2012), who reported that common DNA variants in specific candidate genes were associated with altered neural activation in language-related regions of healthy individuals that carried them. In particular, different single-nucleotide polymorphisms (SNPs) of FOXP2 correlated with variation in task-based activation in left inferior frontal and precentral gyri, whereas a SNP at the KIAA0319/TTRAP/THEM2 locus was associated with variable functional asymmetry of the superior temporal sulcus. Here, we directly test each claim using a closely matched neuroimaging genetics approach in independent cohorts comprising 427 participants, four times larger than the original study of 94 participants. Despite demonstrating power to detect associations with substantially smaller effect sizes than those of the original report, we do not replicate any of the reported associations. Moreover, formal Bayesian analyses reveal substantial to strong evidence in support of the null hypothesis (no effect). We highlight key aspects of the original investigation, common to functional neuroimaging genetics studies, which could have yielded elevated false-positive rates. Genetic accounts of individual differences in cognitive functional neuroimaging are likely to be as complex as behavioral/cognitive tests, involving many common genetic variants, each of tiny effect. Reliable identification of true biological signals requires large sample sizes, power calculations, and validation in independent cohorts with equivalent paradigms.

SIGNIFICANCE STATEMENT A pervasive idea in neuroscience is that neuroimaging-based measures of brain function, being closer to underlying neurobiology, are more amenable for uncovering links to genetics. This is a core assumption of prominent studies that associate common DNA variants with altered activations in task-based fMRI, despite using samples (10–100 people) that lack power for detecting the tiny effect sizes typical of genetically complex traits. Here, we test central findings from one of the most influential prior studies. Using matching paradigms and substantially larger samples, coupled to power calculations and formal Bayesian statistics, our data strongly refute the original findings. We demonstrate that neuroimaging genetics with task-based fMRI should be subject to the same rigorous standards as studies of other complex traits.

Abstract

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

Abstract

Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.

Abstract

There are more than 7,000 languages spoken in the world today1. It has been argued that the natural and social environment of languages drives this diversity. However, a fundamental question is how strong are environmental pressures, and does neutral drift suffice as a mechanism to explain diversification? We estimate the phylogenetic signals of geographic dimensions, distance to water, climate and population size on more than 6,000 phylogenetic trees of 46 language families. Phylogenetic signals of environmental factors are generally stronger than expected under the null hypothesis of no relationship with the shape of family trees. Importantly, they are also—in most cases—not compatible with neutral drift models of constant-rate change across the family tree branches. Our results suggest that language diversification is driven by further adaptive and non-adaptive pressures. Language diversity cannot be understood without modelling the pressures that physical, ecological and social factors exert on language users in different environments across the globe.

Abstract

One of the best-known types of non-independence between languages is caused by genealogical relationships due to descent from a common ancestor. These can be represented by (more or less resolved and controversial) language family trees. In theory, one can argue that language families should be built through the strict application of the comparative method of historical linguistics, but in practice this is not always the case, and there are several proposed classifications of languages into language families, each with its own advantages and disadvantages. A major stumbling block shared by most of them is that they are relatively difficult to use with computational methods, and in particular with phylogenetics. This is due to their lack of standardization, coupled with the general non-availability of branch length information, which encapsulates the amount of evolution taking place on the family tree. In this paper I introduce a method (and its implementation in R) that converts the language classifications provided by four widely-used databases (Ethnologue, WALS, AUTOTYP and Glottolog) intothe de facto Newick standard generally used in phylogenetics, aligns the four most used conventions for unique identifiers of linguistic entities (ISO 639-3, WALS, AUTOTYP and Glottocode), and adds branch length information from a variety of sources (the tree's own topology, an externally given numeric constant, or a distance matrix). The R scripts, input data and resulting Newick trees are available under liberal open-source licenses in a GitHub repository (https://github.com/ddediu/lgfam-newick), to encourage and promote the use of phylogenetic methods to investigate linguistic diversity and its temporal dynamics.

Abstract

Here we re-evaluate our 2013 paper on the antiquity of language (Dediu and Levinson, 2013) in the light of a surge of new information on human evolution in the last half million years. Although new genetic data suggest the existence of some cognitive differences between Neanderthals and modern humans — fully expected after hundreds of thousands of years of partially separate evolution, overall our claims that Neanderthals were fully articulate beings and that language evolution was gradual are further substantiated by the wealth of new genetic, paleontological and archeological evidence briefly reviewed here.

Abstract

Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA-binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language deficits. Our findings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD.

Abstract

Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

Abstract

FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo- and hetero-dimers with each other. Physical associations with other transcription factors might also modulate the functions of FOXP proteins. However, few FOXP-interacting transcription factors have been identified so far. Therefore, we sought to discover additional transcription factors that interact with the brain-expressed FOXP proteins, FOXP1, FOXP2 and FOXP4, through affinity-purifications of protein complexes followed by mass spectrometry. We identified seven novel FOXP-interacting transcription factors (NR2F1, NR2F2, SATB1, SATB2, SOX5, YY1 and ZMYM2), five of which have well-established roles in cortical development. Accordingly, we found that these transcription factors are co-expressed with FoxP2 in the deep layers of the cerebral cortex and also in the Purkinje cells of the cerebellum, suggesting that they may cooperate with the FoxPs to regulate neural gene expression in vivo. Moreover, we demonstrated that etiological mutations of FOXP1 and FOXP2, known to cause neurodevelopmental disorders, severely disrupted the interactions with FOXP-interacting transcription factors. Additionally, we pinpointed specific regions within FOXP2 sequence involved in mediating these interactions. Thus, by expanding the FOXP interactome we have uncovered part of a broader neural transcription factor network involved in cortical development, providing novel molecular insights into the transcriptional architecture underlying brain development and neurodevelopmental disorders.

Abstract

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent–offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

Abstract

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.

Abstract

Computer models of cultural evolution have shown language properties emerging on interacting agents with a brain that lacks dedicated, nativist language modules. Notably, models using Bayesian agents provide a precise specification of (extra-)liguististic factors (e.g., genetic) that shape language through iterated learning (biases on language), and demonstrate that weak biases get expressed more strongly over time (bias amplification). Other models attempt to lessen assumption on agents’ innate predispositions even more, and emphasize self-organization within agents, highlighting glossogenesis (the development of language from a nonlinguistic state). Ultimately however, one also has to recognize that biology and culture are strongly interacting, forming a coevolving system. As such, computer models show that agents might (biologically) evolve to a state predisposed to language adaptability, where (culturally) stable language features might get assimilated into the genome via Baldwinian niche construction. In summary, while many questions about language evolution remain unanswered, it is clear that it is not to be completely understood from a purely biological, cognitivist perspective. Language should be regarded as (partially) emerging on the social interactions between large populations of speakers. In this context, agent models provide a sound approach to investigate the complex dynamics of genetic biasing on language and speech

Abstract

People vary at most levels, from the molecular to the cognitive, and the shape of the hard palate (the bony roof of the mouth) is no exception. The patterns of variation in the hard palate are important for the forensic sciences and (palaeo)anthropology, and might also play a role in speech production, both in pathological cases and normal variation. Here we describe a method based on Bézier curves, whose main aim is to generate possible shapes of the hard palate in humans for use in computer simulations of speech production and language evolution. Moreover, our method can also capture existing patterns of variation using few and easy-to-interpret parameters, and fits actual data obtained from MRI traces very well with as little as two or three free parameters. When compared to the widely-used Principal Component Analysis (PCA), our method fits actual data slightly worse for the same number of degrees of freedom. However, it is much better at generating new shapes without requiring a calibration sample, its parameters have clearer interpretations, and their ranges are grounded in geometrical considerations. © 2018 Janssen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

Abstract

Statistical inference plays a critical role in modern scientific research, however, the dominant method for statistical inference in science, null hypothesis significance testing (NHST), is often misunderstood and misused, which leads to unreproducible findings. To address this issue, researchers propose to adopt the Bayes factor as an alternative to NHST. The Bayes factor is a principled Bayesian tool for model selection and hypothesis testing, and can be interpreted as the strength for both the null hypothesis H0 and the alternative hypothesis H1 based on the current data. Compared to NHST, the Bayes factor has the following advantages: it quantifies the evidence that the data provide for both the H0 and the H1, it is not “violently biased” against H0, it allows one to monitor the evidence as the data accumulate, and it does not depend on sampling plans. Importantly, the recently developed open software JASP makes the calculation of Bayes factor accessible for most researchers in psychology, as we demonstrated for the t-test. Given these advantages, adopting the Bayes factor will improve psychological researchers’ statistical inferences. Nevertheless, to make the analysis more reproducible, researchers should keep their data analysis transparent and open.

Abstract

Left-right laterality is an important aspect of human –and in fact all vertebrate– brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.

Abstract

Left-right asymmetry is subtle but pervasive in the human central nervous system. This asymmetry is initiated early during development, but its mechanisms are poorly known. Forebrains and midbrains were dissected from six human embryos at Carnegie stages 15 or 16, one of which was female. The structures were divided into left and right sides, and RNA was isolated. RNA was sequenced with 100 base-pair paired ends using Illumina Hiseq 4000. After quality control, five paired brain sides were available for midbrain and forebrain. A paired analysis between left- and right sides of a given brain structure across the embryos identified left-right differences. The dataset, consisting of Fastq files and a read count table, can be further used to study early development of the human brain

Abstract

The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence. SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.

Abstract

Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder (MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia (FES), 125 with MDD, and 237 demographically-matched healthy controls (HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with a one-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD. Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.

Abstract

Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.

Abstract

Background

Autism is a dimensional condition, representing the extreme end of a continuum of social competence that extends throughout the general population. Currently, little is known about how autistic social traits (ASTs), measured across the full spectrum of severity, develop during childhood and adolescence, including whether there are developmental differences between boys and girls. Therefore, we sought to chart the trajectories of ASTs in the general population across childhood and adolescence, with a focus on gender differences.
Methods

Participants were 9,744 males (n = 4,784) and females (n = 4,960) from ALSPAC, a UK birth cohort study. ASTs were assessed when participants were aged 7, 10, 13 and 16 years, using the parent‐report Social Communication Disorders Checklist. Data were modelled using latent growth curve analysis.
Results

Developmental trajectories of males and females were nonlinear, showing a decline from 7 to 10 years, followed by an increase between 10 and 16 years. At 7 years, males had higher levels of ASTs than females (mean raw score difference = 0.88, 95% CI [.72, 1.04]), and were more likely (odds ratio [OR] = 1.99; 95% CI, 1.82, 2.16) to score in the clinical range on the SCDC. By 16 years this gender difference had disappeared: males and females had, on average, similar levels of ASTs (mean difference = 0.00, 95% CI [−0.19, 0.19]) and were equally likely to score in the SCDC's clinical range (OR = 0.91, 95% CI, 0.73, 1.10). This was the result of an increase in females’ ASTs between 10 and 16 years.
Conclusions

There are gender‐specific trajectories of autistic social impairment, with females more likely than males to experience an escalation of ASTs during early‐ and midadolescence. It remains to be discovered whether the observed female adolescent increase in ASTs represents the genuine late onset of social difficulties or earlier, subtle, pre‐existing difficulties becoming more obvious.

Abstract

Recurrent deletions of a ~600-kb region of 16p11.2 have been associated with a highly penetrant form of childhood apraxia of speech (CAS). Yet prior findings have been based on a small, potentially biased sample using retrospectively collected data. We examine the prevalence of CAS in a larger cohort of individuals with 16p11.2 deletion using a prospectively designed assessment battery. The broader speech and language phenotype associated with carrying this deletion was also examined. 55 participants with 16p11.2 deletion (47 children, 8 adults) underwent deep phenotyping to test for the presence of CAS and other speech and language diagnoses. Standardized tests of oral motor functioning, speech production, language, and non-verbal IQ were conducted. The majority of children (77%) and half of adults (50%) met criteria for CAS. Other speech outcomes were observed including articulation or phonological errors (i.e., phonetic and cognitive-linguistic errors, respectively), dysarthria (i.e., neuromuscular speech disorder), minimal verbal output, and even typical speech in some. Receptive and expressive language impairment was present in 73% and 70% of children, respectively. Co-occurring neurodevelopmental conditions (e.g., autism) and non-verbal IQ did not correlate with the presence of CAS. Findings indicate that CAS is highly prevalent in children with 16p11.2 deletion with symptoms persisting into adulthood for many. Yet CAS occurs in the context of a broader speech and language profile and other neurobehavioral deficits. Further research will elucidate specific genetic and neural pathways leading to speech and language deficits in individuals with 16p11.2 deletions, resulting in more targeted speech therapies addressing etiological pathways.

Abstract

Communication disorder is common in Koolen de Vries syndrome (KdVS), yet its specific symptomatology has not been examined, limiting prognostic counselling and application of targeted therapies. Here we examine the communication phenotype associated with KdVS. Twenty-nine participants (12 males, 4 with KANSL1 variants, 25 with 17q21.31 microdeletion), aged 1.0–27.0 years were assessed for oral-motor, speech, language, literacy, and social functioning. Early history included hypotonia and feeding difficulties. Speech and language development was delayed and atypical from onset of first words (2; 5–3; 5 years of age on average). Speech was characterised by apraxia (100%) and dysarthria (93%), with stuttering in some (17%). Speech therapy and multi-modal communication (e.g., sign-language) was critical in preschool. Receptive and expressive language abilities were typically commensurate (79%), both being severely affected relative to peers. Children were sociable with a desire to communicate, although some (36%) had pragmatic impairments in domains, where higher-level language was required. A common phenotype was identified, including an overriding ‘double hit’ of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development. Remarkably however, speech prognosis was positive; apraxia resolved, and although dysarthria persisted, children were intelligible by mid-to-late childhood. In contrast, language and literacy deficits persisted, and pragmatic deficits were apparent. Children with KdVS require early, intensive, speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate. Greater understanding of the linguistic phenotype may help unravel the relevance of KANSL1 to child speech and language development.

Abstract

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy–like phenotype in a subset of patients.

Abstract

Background: Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert their maximum influence during different periods of development. This includes analyses of social-communciation difficulties that share, depending on their developmental stage, stronger genetic links with either Autism Spectrum Disorder or schizophrenia. Here we developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social-communication difficulties, during a ~10-year period spanning childhood and adolescence. Methods: Longitudinally assessed quantitative social-communication problems (N ≤ 5,551) were studied in participants from a UK birth cohort (ALSPAC, 8 to 17 years). Using standardised measures, genetic architectures were investigated with novel multivariate genetic-relationship-matrix structural equation models (GSEM) incorporating whole-genome genotyping information. Analogous to twin research, GSEM included Cholesky decomposition, common pathway and independent pathway models. Results: A 2-factor Cholesky decomposition model described the data best. One genetic factor was common to SCDC measures across development, the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Importantly, genetic factors operating at 8 years explained only ~50% of the genetic variation at 17 years. Conclusion: Using latent factor models, we identified developmental changes in the genetic architecture of social-communication difficulties that enhance the understanding of ASD and schizophrenia-related dimensions. More generally, GSEM present a framework for modelling shared genetic aetiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap

Abstract

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and
schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic in fluences between these clinical conditions and impairments in social communication depends on
the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth
(Avon Longitudinal Study of Parents and Children,N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social
Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases,
11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the
Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic in fluences between ASD and social
communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of
genetic factors in fluencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic in fluences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms

Abstract

Chromatin remodeling is of crucial importance during brain development. Pathogenic
alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental
disorders. We describe an index case with a de novo missense mutation in CHD3,
identified during whole genome sequencing of a cohort of children with rare speech disorders.
To gain a comprehensive view of features associated with disruption of this gene, we use a
genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3
mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase
domain of the encoded protein. Modeling their impact on the three-dimensional structure
demonstrates disturbance of critical binding and interaction motifs. Experimental assays with
six of the identified mutations show that a subset directly affects ATPase activity, and all but
one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a
syndrome characterized by intellectual disability, macrocephaly, and impaired speech and
language.

Abstract

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes

Abstract

Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

Abstract

Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive.