Publications

Abstract

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6–19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06–1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Abstract

Pairwise maximum likelihood (PML) estimation is a promising method for multilevel models with discrete responses. Multilevel models take into account that units within a cluster tend to be more alike than units from different clusters. The pairwise likelihood is then obtained as the product of bivariate likelihoods for all within-cluster pairs of units and items. In this study, we investigate the PML estimation method with computationally intensive multilevel random intercept and random slope structural equation models (SEM) in discrete data. In pursuing this, we first reconsidered the general ‘wide format’ (WF) approach for SEM models and then extend the WF approach with random slopes. In a small simulation study we the determine accuracy and efficiency of the PML estimation method by varying the sample size (250, 500, 1000, 2000), response scales (two-point, four-point), and data-generating model (mediation model with three random slopes, factor model with one and two random slopes). Overall, results show that the PML estimation method is capable of estimating computationally intensive random intercept and random slopes multilevel models in the SEM framework with discrete data and many (six or more) latent variables with satisfactory accuracy and efficiency. However, the condition with 250 clusters combined with a two-point response scale shows more bias.

Abstract

The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands. A total of 858 probands were collected from 26 centers, of whom 722 carried no or one pathogenic ABCA4 variant while 136 cases carried two ABCA4 alleles, one of which was a frequent mild variant, suggesting that deep-intronic variants (DIVs) or other cis-modifiers might have been missed. After single molecule molecular inversion probes (smMIPs)-based sequencing of the complete 128-kb ABCA4 locus, the effect of putative splice variants was assessed in vitro by midigene splice assays in HEK293T cells. The breakpoints of copy number variants (CNVs) were determined by junction PCR and Sanger sequencing. ABCA4 sequence analysis solved 207/520 (39.8%) naïve or unsolved cases and 70/202 (34.7%) monoallelic cases, while additional causal variants were identified in 54/136 (39.7%) of probands carrying two variants. Seven novel DIVs and six novel non-canonical splice site variants were detected in a total of 35 alleles and characterized, including the c.6283-321C>G variant leading to a complex splicing defect. Additionally, four novel CNVs were identified and characterized in five alleles. These results confirm that smMIPs-based sequencing of the complete ABCA4 gene provides a cost-effective method to genetically solve retinopathy cases and that several rare structural and splice altering defects remain undiscovered in STGD1 cases.

Abstract

Several molecular and phenotypic algorithms exist that establish genotype–phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore’s ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype–phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.

Abstract

Lifelong graph learning deals with the problem of continually adapting graph neural network (GNN) models to changes in evolving graphs. We address two critical challenges of lifelong graph learning in this work: dealing with new classes and tackling imbalanced class distributions. The combination of these two challenges is particularly relevant since newly emerging classes typically resemble only a tiny fraction of the data, adding to the already skewed class distribution. We make several contributions: First, we show that the amount of unlabeled data does not influence the results, which is an essential prerequisite for lifelong learning on a sequence of tasks. Second, we experiment with different label rates and show that our methods can perform well with only a tiny fraction of annotated nodes. Third, we propose the gDOC method to detect new classes under the constraint of having an imbalanced class distribution. The critical ingredient is a weighted binary cross-entropy loss function to account for the class imbalance. Moreover, we demonstrate combinations of gDOC with various base GNN models such as GraphSAGE, Simplified Graph Convolution, and Graph Attention Networks. Lastly, our k-neighborhood time difference measure provably normalizes the temporal changes across different graph datasets. With extensive experimentation, we find that the proposed gDOC method is consistently better than a naive adaption of DOC to graphs. Specifically, in experiments using the smallest history size, the out-of-distribution detection score of gDOC is 0.09 compared to 0.01 for DOC. Furthermore, gDOC achieves an Open-F1 score, a combined measure of in-distribution classification and out-of-distribution detection, of 0.33 compared to 0.25 of DOC (32% increase).

Abstract

Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positive selection of predisposing loci. Furthermore, evolutionary pressures on schizophrenia risk alleles could have changed throughout human history as new environments emerged. Here in this study, we used 1000 Genomes Project data to explore the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures after the human diaspora out of Africa around 100,000 years ago on a genome-wide scale. We found evidence for significant enrichment of RNS markers in derived alleles arisen during human evolution conferring protection to schizophrenia. Moreover, both partitioned heritability and gene set enrichment analyses of mapped genes from schizophrenia predisposing loci subject to RNS revealed a lower involvement in brain and neuronal related functions compared to those not subject to RNS. Taken together, our results suggest non-antagonistic pleiotropy as a likely mechanism behind RNS that could explain the persistence of schizophrenia common predisposing variation in human populations due to its association to other non-psychiatric phenotypes.

Abstract

The search for molecular underpinnings of human vocal communication has focused on genes encoding forkhead-box transcription factors, as rare disruptions of FOXP1, FOXP2, and FOXP4 have been linked to disorders involving speech and language deficits. In male songbirds, an animal model for vocal learning, experimentally altered expression levels of these transcription factors impair song production learning. The relative contributions of auditory processing, motor function or auditory-motor integration to the deficits observed after different FoxP manipulations in songbirds are unknown. To examine the potential effects on auditory learning and development, we focused on female zebra finches (Taeniopygia guttata) that do not sing but develop song memories, which can be assayed in operant preference tests. We tested whether the relatively high levels of FoxP1 expression in forebrain areas implicated in female song preference learning are crucial for the development and/or maintenance of this behavior. Juvenile and adult female zebra finches received FoxP1 knockdowns targeted to HVC (proper name) or to the caudomedial mesopallium (CMM). Irrespective of target site and whether the knockdown took place before (juveniles) or after (adults) the sensitive phase for song memorization, all groups preferred their tutor’s song. However, adult females with FoxP1 knockdowns targeted at HVC showed weaker motivation to hear song and weaker song preferences than sham-treated controls, while no such differences were observed after knockdowns in CMM or in juveniles. In summary, FoxP1 knockdowns in the cortical song nucleus HVC were not associated with impaired tutor song memory but reduced motivation to actively request tutor songs.

Abstract

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.

Abstract

The expansion of the cerebral cortex is one of the most distinctive changes in the evolution of the human brain. Cortical expansion and related increases in cortical folding may have contributed to emergence of our capacities for high-order cognitive abilities. Molecular analysis of humans, archaic hominins, and non-human primates has allowed identification of chromosomal regions showing evolutionary changes at different points of our phylogenetic history. In this study, we assessed the contributions of genomic annotations spanning 30 million years to human sulcal morphology measured via MRI in more than 18,000 participants from the UK Biobank. We found that variation within brain-expressed human gained enhancers, regulatory genetic elements that emerged since our last common ancestor with Old World monkeys, explained more trait heritability than expected for the left and right calloso-marginal posterior fissures and the right central sulcus. Intriguingly, these are sulci that have been previously linked to the evolution of locomotion in primates and later on bipedalism in our hominin ancestors.

Abstract

Background
Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition.

Methods
Here we phenotyped 29 individuals from 18 families with pathogenic FOXP2-only variants (13 loss-of-function, 5 missense variants; 14 males; aged 2 years to 62 years). Health and development (cognitive, motor, social domains) was examined, including speech and language outcomes with the first cross-linguistic analysis of English and German.

Results
Speech disorders were prevalent (24/26, 92%) and CAS was most common (23/26, 89%), with similar speech presentations across English and German. Speech was still impaired in adulthood and some speech sounds (e.g. ‘th’, ‘r’, ‘ch’, ‘j’) were never acquired. Language impairments (22/26, 85%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (14/27, 52%) and gross (14/27, 52%) motor impairment, anxiety (6/28, 21%), depression (7/28, 25%), and sleep disturbance (11/15, 44%). Physical features were common (23/28, 82%) but with no consistent pattern. Cognition ranged from average to mildly impaired, and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition.

Conclusions
Although we identify increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared to other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entrypoint for examining the neurobiological bases of speech disorder.

Abstract

Mice display a wide repertoire of vocalizations that varies with sex, strain, and context. Especially during social interaction, including sexually motivated dyadic interaction, mice emit sequences of ultrasonic vocalizations (USVs) of high complexity. As animals of both sexes vocalize, a reliable attribution of USVs to their emitter is essential. The state-of-the-art in sound localization for USVs in 2D allows spatial localization at a resolution of multiple centimeters. However, animals interact at closer ranges, e.g. snout-to-snout. Hence, improved algorithms are required to reliably assign USVs. We present a novel algorithm, SLIM (Sound Localization via Intersecting Manifolds), that achieves a 2–3-fold improvement in accuracy (13.1–14.3 mm) using only 4 microphones and extends to many microphones and localization in 3D. This accuracy allows reliable assignment of 84.3% of all USVs in our dataset. We apply SLIM to courtship interactions between adult C57Bl/6J wildtype mice and those carrying a heterozygous Foxp2 variant (R552H). The improved spatial accuracy reveals that vocalization behavior is dependent on the spatial relation between the interacting mice. Female mice vocalized more in close snout-to-snout interaction while male mice vocalized more when the male snout was in close proximity to the female's ano-genital region. Further, we find that the acoustic properties of the ultrasonic vocalizations (duration, Wiener Entropy, and sound level) are dependent on the spatial relation between the interacting mice as well as on the genotype. In conclusion, the improved attribution of vocalizations to their emitters provides a foundation for better understanding social vocal behaviors.

Abstract

Background

Autistic people show diverse trajectories of autistic traits over time, a phenomenon labelled ‘chronogeneity’. For example, some show a decrease in symptoms, whilst others experience an intensification of difficulties. Autism spectrum disorder (ASD) is a dimensional condition, representing one end of a trait continuum that extends throughout the population. To date, no studies have investigated chronogeneity across the full range of autistic traits. We investigated the nature and clinical significance of autism trait chronogeneity in a large, general population sample.
Methods

Autistic social/communication traits (ASTs) were measured in the Avon Longitudinal Study of Parents and Children using the Social and Communication Disorders Checklist (SCDC) at ages 7, 10, 13 and 16 (N = 9744). We used Growth Mixture Modelling (GMM) to identify groups defined by their AST trajectories. Measures of ASD diagnosis, sex, IQ and mental health (internalising and externalising) were used to investigate external validity of the derived trajectory groups.
Results

The selected GMM model identified four AST trajectory groups: (i) Persistent High (2.3% of sample), (ii) Persistent Low (83.5%), (iii) Increasing (7.3%) and (iv) Decreasing (6.9%) trajectories. The Increasing group, in which females were a slight majority (53.2%), showed dramatic increases in SCDC scores during adolescence, accompanied by escalating internalising and externalising difficulties. Two-thirds (63.6%) of the Decreasing group were male.
Conclusions

Clinicians should note that for some young people autism-trait-like social difficulties first emerge during adolescence accompanied by problems with mood, anxiety, conduct and attention. A converse, majority-male group shows decreasing social difficulties during adolescence.

Abstract

Human communication involves the process of translating intentions into communicative actions. But how exactly do our intentions surface in the visible communicative behavior we display? Here we focus on pointing gestures, a fundamental building block of everyday communication, and investigate whether and how different types of underlying intent modulate the kinematics of the pointing hand and the brain activity preceding the gestural movement. In a dynamic virtual reality environment, participants pointed at a referent to either share attention with their addressee, inform their addressee, or get their addressee to perform an action. Behaviorally, it was observed that these different underlying intentions modulated how long participants kept their arm and finger still, both prior to starting the movement and when keeping their pointing hand in apex position. In early planning stages, a neurophysiological distinction was observed between a gesture that is used to share attitudes and knowledge with another person versus a gesture that mainly uses that person as a means to perform an action. Together, these findings suggest that our intentions influence our actions from the earliest neurophysiological planning stages to the kinematic endpoint of the movement itself.

Abstract

The structural design features of human language emerge in the process of cultural evolution, shaping languages over the course of communication, learning, and transmission. What role does this leave biological evolution? This chapter highlights the biological bases and preconditions that underlie the particular type of prosocial behaviours and cognitive inference abilities that are required for languages to emerge via cultural evolution to begin with.

Abstract

Humans are unique in their sophisticated culture and societal structures, their complex languages, and their extensive tool use. According to the human self-domestication hypothesis, this unique set of traits may be the result of an evolutionary process of self-induced domestication, in which humans evolved to be less aggressive and more cooperative. However, the only other species that has been argued to be self-domesticated besides humans so far is bonobos, resulting in a narrow scope for investigating this theory limited to the primate order. Here, we propose an animal model for studying self-domestication: the elephant. First, we support our hypothesis with an extensive cross-species comparison, which suggests that elephants indeed exhibit many of the features associated with self-domestication (e.g., reduced aggression, increased prosociality, extended juvenile period, increased playfulness, socially regulated cortisol levels, and complex vocal behavior). Next, we present genetic evidence to reinforce our proposal, showing that genes positively selected in elephants are enriched in pathways associated with domestication traits and include several candidate genes previously associated with domestication. We also discuss several explanations for what may have triggered a self-domestication process in the elephant lineage. Our findings support the idea that elephants, like humans and bonobos, may be self-domesticated. Since the most recent common ancestor of humans and elephants is likely the most recent common ancestor of all placental mammals, our findings have important implications for convergent evolution beyond the primate taxa, and constitute an important advance toward understanding how and why self-domestication shaped humans’ unique cultural niche.

Abstract

Cortical asymmetry is a ubiquitous feature of brain organization that is altered in neurodevelopmental disorders and aging. Achieving consensus on cortical asymmetries in humans is necessary to uncover the genetic-developmental mechanisms that shape them and factors moderating cortical lateralization. Here, we delineate population-level asymmetry in cortical thickness and surface area vertex-wise in 7 datasets and chart asymmetry trajectories across life (4-89 years; observations = 3937; 70% longitudinal). We reveal asymmetry interrelationships, heritability, and test associations in UK Biobank (N=∼37,500). Cortical asymmetry was robust across datasets. Whereas areal asymmetry is predominantly stable across life, thickness asymmetry grows in development and declines in aging. Areal asymmetry correlates in specific regions, whereas thickness asymmetry is globally interrelated across cortex and suggests high directional variability in global thickness lateralization. Areal asymmetry is moderately heritable (max h2SNP ∼19%), and phenotypic correlations are reflected by high genetic correlations, whereas heritability of thickness asymmetry is low. Finally, we detected an asymmetry association with cognition and confirm recently-reported handedness links. Results suggest areal asymmetry is developmentally stable and arises in early life, whereas developmental changes in thickness asymmetry may lead to directional variability of global thickness lateralization. Our results bear enough reproducibility to serve as a standard for future brain asymmetry studies.

Abstract

Purpose: To determine the disease pathogenesis associated with the frequent ABCA4 variant c.5714+5G>A (p.[=,Glu1863Leufs*33]).

Methods: Patient-derived photoreceptor precursor cells were generated to analyze the effect of c.5714+5G>A on splicing and perform a quantitative analysis of c.5714+5G>A products. Patients with c.5714+5G>A in trans with a null allele (i.e., c.5714+5G>A patients; n = 7) were compared with patients with two null alleles (i.e., double null patients; n = 11); with a special attention to the degree of RPE atrophy (area of definitely decreased autofluorescence and the degree of photoreceptor impairment (outer nuclear layer thickness and pattern electroretinography amplitude).

Results: RT-PCR of mRNA from patient-derived photoreceptor precursor cells showed exon 40 and exon 39/40 deletion products, as well as the normal transcript. Quantification of products showed 52.4% normal and 47.6% mutant ABCA4 mRNA. Clinically, c.5714+5G>A patients displayed significantly better structural and functional preservation of photoreceptors (thicker outer nuclear layer, presence of tubulations, higher pattern electroretinography amplitude) than double null patients with similar degrees of RPE loss, whereas double null patients exhibited signs of extensive photoreceptor ,damage even in the areas with preserved RPE.

Conclusions: The prototypical STGD1 sequence of events of primary RPE and secondary photoreceptor damage is congruous with c.5714+5G>A, but not the double null genotype, which implies different and genotype-dependent disease mechanisms. We hypothesize that the relative photoreceptor sparing in c.5714+5G>A patients results from the remaining function of the ABCA4 transporter originating from the normally spliced product, possibly by decreasing the direct bisretinoid toxicity on photoreceptor membranes.

Abstract

Left–right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case–control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case–control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case–control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case–control status. Subtle case–control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Abstract

White matter tracts form the structural basis of large-scale brain networks. We applied brain-wide tractography to diffusion images from 30,810 adults (U.K. Biobank) and found significant heritability for 90 node-level and 851 edge-level network connectivity measures. Multivariate genome-wide association analyses identified 325 genetic loci, of which 80% had not been previously associated with brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia, and neurons. The multivariate association profiles implicated 31 loci in connectivity between core regions of the left-hemisphere language network. Polygenic scores for psychiatric, neurological, and behavioral traits also showed significant multivariate associations with structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to variation in the structural connectome of the human brain.

Abstract

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals, and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (N=11), intellectual disability (N=9), epilepsy (N=7) and autism spectrum disorder (N=4). Additional phenotypic features included abnormal growth parameters (N=7), heart anomalies (N=2) and hearing loss (N=2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

Abstract

Background: The hypothalamus-pituitary-thyroid axis coordinates brain development and postdevelopmental function. Thyroid hormone (TH) variations, even within the normal range, have been associated with the risk of developing common psychiatric disorders, although the underlying mechanisms remain poorly understood.

Methods: To get new insight into the potentially shared mechanisms underlying thyroid dysfunction and psychiatric disorders, we performed a comprehensive analysis of multiple phenotypic and genotypic databases. We investigated the relationship of thyroid disorders with depression, bipolar disorder (BIP), and anxiety disorders (ANXs) in 497,726 subjects from U.K. Biobank. We subsequently investigated genetic correlations between thyroid disorders, thyrotropin (TSH), and free thyroxine (fT4) levels, with the genome-wide factors that predispose to psychiatric disorders. Finally, the observed global genetic correlations were furthermore pinpointed to specific local genomic regions.

Results: Hypothyroidism was positively associated with an increased risk of major depressive disorder (MDD; OR = 1.31, p = 5.29 × 10−89), BIP (OR = 1.55, p = 0.0038), and ANX (OR = 1.16, p = 6.22 × 10−8). Hyperthyroidism was associated with MDD (OR = 1.11, p = 0.0034) and ANX (OR = 1.34, p = 5.99 × 10−⁶). Genetically, strong coheritability was observed between thyroid disease and both major depressive (rg = 0.17, p = 2.7 × 10−⁴) and ANXs (rg = 0.17, p = 6.7 × 10−⁶). This genetic correlation was particularly strong at the major histocompatibility complex locus on chromosome 6 (p < 10−⁵), but further analysis showed that other parts of the genome also contributed to this global effect. Importantly, neither TSH nor fT4 levels were genetically correlated with mood disorders.

Conclusions: Our findings highlight an underlying association between autoimmune hypothyroidism and mood disorders, which is not mediated through THs and in which autoimmunity plays a prominent role. While these findings could shed new light on the potential ineffectiveness of treating (minor) variations in thyroid function in psychiatric disorders, further research is needed to identify the exact underlying molecular mechanisms.

Abstract

TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein–protein interaction.

Abstract

When experienced in-person, engagement with art has been associated with positive outcomes in well-being and mental health. However, especially in the last decade, art viewing, cultural engagement, and even ‘trips’ to museums have begun to take place online, via computers, smartphones, tablets, or in virtual reality. Similarly, to what has been reported for in-person visits, online art engagements—easily accessible from personal devices—have also been associated to well-being impacts. However, a broader understanding of for whom and how online-delivered art might have well-being impacts is still lacking. In the present study, we used a Monet interactive art exhibition from Google Arts and Culture to deepen our understanding of the role of pleasure, meaning, and individual differences in the responsiveness to art. Beyond replicating the previous group-level effects, we confirmed our pre-registered hypothesis that trait-level inter-individual differences in aesthetic responsiveness predict some of the benefits that online art viewing has on well-being and further that such inter-individual differences at the trait level were mediated by subjective experiences of pleasure and especially meaningfulness felt during the online-art intervention. The role that participants' experiences play as a possible mechanism during art interventions is discussed in light of recent theoretical models.

Abstract

What determines the aesthetic appeal of artworks? Recent work suggests that aesthetic appeal can, to some extent, be predicted from a visual artwork’s image features. Yet a large fraction of variance in aesthetic ratings remains unexplained and may relate to individual preferences. We hypothesized that an artwork’s aesthetic appeal depends strongly on self-relevance. In a first study (N = 33 adults, online replication N = 208), rated aesthetic appeal for real artworks was positively predicted by rated self-relevance. In a second experiment (N = 45 online), we created synthetic, self-relevant artworks using deep neural networks that transferred the style of existing artworks to photographs. Style transfer was applied to self-relevant photographs selected to reflect participant-specific attributes such as autobiographical memories. Self-relevant, synthetic artworks were rated as more aesthetically appealing than matched control images, at a level similar to human-made artworks. Thus, self-relevance is a key determinant of aesthetic appeal, independent of artistic skill and image features.

Abstract

Laterality indices (LIs) quantify the left-right asymmetry of brain and behavioural variables and provide a measure that is statistically convenient and seemingly easy to interpret. Substantial variability in how structural and functional asymmetries are recorded, calculated, and reported, however, suggest little agreement on the conditions required for its valid assessment. The present study aimed for consensus on general aspects in this context of laterality research, and more specifically within a particular method or technique (i.e., dichotic listening, visual half-field technique, performance asymmetries, preference bias reports, electrophysiological recording, functional MRI, structural MRI, and functional transcranial Doppler sonography). Experts in laterality research were invited to participate in an online Delphi survey to evaluate consensus and stimulate discussion. In Round 0, 106 experts generated 453 statements on what they considered good practice in their field of expertise. Statements were organised into a 295-statement survey that the experts then were asked, in Round 1, to independently assess for importance and support, which further reduced the survey to 241 statements that were presented again to the experts in Round 2. Based on the Round 2 input, we present a set of critically reviewed key recommendations to record, assess, and report laterality research for various methods.

Abstract

Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.

Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Abstract

The primary aim of this paper is to assess patterns of morphological variation in the mandible to investigate changes during the last 500 years in the Netherlands. Three-dimensional geometric morphometrics is used on data collected from adults from three populations living in the Netherlands during three time-periods. Two of these samples come from Dutch archaeological sites (Alkmaar, 1484-1574, n = 37; and Middenbeemster, 1829-1866, n = 51) and were digitized using a 3D laser scanner. The third is a modern sample obtained from MRI scans of 34 modern Dutch individuals. Differences between mandibles are dominated by size. Significant differences in size are found among samples, with on average, males from Alkmaar having the largest mandibles and females from Middenbeemster having the smallest. The results are possibly linked to a softening of the diet, due to a combination of differences in food types and food processing that occurred between these time-periods. Differences in shape are most noticeable between males from Alkmaar and Middenbeemster. Shape differences between males and females are concentrated in the symphysis and ramus, which is mostly the consequence of sexual dimorphism. The relevance of this research is a better understanding of the anatomical variation of the mandible that can occur over an evolutionarily short time, as well as supporting research that has shown plasticity of the mandibular form related to diet and food processing. This plasticity of form must be taken into account in phylogenetic research and when the mandible is used in sex estimation of skeletons.

Abstract

Dyslexia is a common specific learning disability with a substantive genetic component. Several candidate genes have been proposed to be implicated in dyslexia susceptibility, such as DYX1C1, ROBO1, KIAA0319, and DCDC2. Associations with variants in these genes have also been reported with a variety of psychometric measures tapping into the underlying processes that might be impaired in dyslexic people. In this study, we first conducted a literature review to select single nucleotide polymorphisms (SNPs) in dyslexia candidate genes that had been repeatedly implicated across studies. We then assessed the SNPs for association in the richly phenotyped longitudinal data set from the Dutch Dyslexia Program. We tested for association with several quantitative traits, including word and nonword reading fluency, rapid naming, phoneme deletion, and nonword repetition. In this, we took advantage of the longitudinal nature of the sample to examine if associations were stable across four educational time-points (from 7 to 12 years). Two SNPs in the KIAA0319 gene were nominally associated with rapid naming, and these associations were stable across different ages. Genetic association analysis with complex cognitive traits can be enriched through the use of longitudinal information on trait development.

Abstract

A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.

Abstract

Language is not a purely cultural phenomenon somehow isolated from its wider environment, and we may only understand its origins and evolution by seriously considering its embedding in this environment as well as its multimodal nature. By environment here we understand other aspects of culture (such as communication technology, attitudes towards language contact, etc.), of the physical environment (ultraviolet light incidence, air humidity, etc.), and of the biological infrastructure for language and speech. We are specifically concerned in this paper with the latter, in the form of the biases, constraints and affordances that the anatomy and physiology of the vocal tract create on speech and language. In a nutshell, our argument is that (a) there is an under-appreciated amount of inter-individual variation in vocal tract (VT) anatomy and physiology, (b) variation that is non-randomly distributed across populations, and that (c) results in systematic differences in phonetics and phonology between languages. Relevant differences in VT anatomy include the overall shape of the hard palate, the shape of the alveolar ridge, the relationship between the lower and upper jaw, to mention just a few, and our data offer a new way to systematically explore such differences and their potential impact on speech. These differences generate very small biases that nevertheless can be amplified by the repeated use and transmission of language, affecting language diachrony and resulting in cross-linguistic synchronic differences. Moreover, the same type of biases and processes might have played an essential role in the emergence and evolution of language, and might allow us a glimpse into the speech and language of extinct humans by, for example, reconstructing the anatomy of parts of their vocal tract from the fossil record and extrapolating the biases we find in present-day humans.

Abstract

Investigation of the biological basis of human speech and language is being transformed by developments in molecular technologies, including high-throughput genotyping and next-generation sequencing of whole genomes. These advances are shedding new light on the genetic architecture underlying language-related disorders (speech apraxia, specific language impairment, developmental dyslexia) as well as that contributing to variation in relevant skills in the general population. We discuss how state-of-the-art methods are uncovering a range of genetic mechanisms, from rare mutations of large effect to common polymorphisms that increase risk in a subtle way, while converging on neurogenetic pathways that are shared between distinct disorders. We consider the future of the field, highlighting the unusual challenges and opportunities associated with studying genomics of language-related traits.

Abstract

The post-genomic era is an exciting time for researchers interested in the biology of speech and language. Substantive advances in molecular methodologies have opened up entire vistas of investigation that were not previously possible, or in some cases even imagined. Speculations concerning the origins of human cognitive traits are being transformed into empirically addressable questions, generating specific hypotheses that can be explicitly tested using data collected from both the natural world and experimental settings. In this article, I discuss a number of promising lines of research in this area. For example, the field has begun to identify genes implicated in speech and language skills, including not just disorders but also the normal range of abilities. Such genes provide powerful entry points for gaining insights into neural bases and evolutionary origins, using sophisticated experimental tools from molecular neuroscience and developmental neurobiology. At the same time, sequencing of ancient hominin genomes is giving us an unprecedented view of the molecular genetic changes that have occurred during the evolution of our species. Synthesis of data from these complementary sources offers an opportunity to robustly evaluate alternative accounts of language evolution. Of course, this endeavour remains challenging on many fronts, as I also highlight in the article. Nonetheless, such an integrated approach holds great potential for untangling the complexities of the capacities that make us human.

Abstract

Neuroimaging measures provide useful endophenotypes for tracing genetic effects on reading and language. A recent Genome-Wide Association Scan Meta-Analysis (GWASMA) of reading and language skills (N = 1862) identified strongest associations with the genes CCDC136/FLNC and RBFOX2. Here, we follow up the top findings from this GWASMA, through neuroimaging genetics in an independent sample of 1275 healthy adults. To minimize multiple-testing, we used a multivariate approach, focusing on cortical regions consistently implicated in prior literature on developmental dyslexia and language impairment. Specifically, we investigated grey matter surface area and thickness of five regions selected a priori: middle temporal gyrus (MTG); pars opercularis and pars triangularis in the inferior frontal gyrus (IFG-PO and IFG-PT); postcentral parietal gyrus (PPG) and superior temporal gyrus (STG). First, we analysed the top associated polymorphisms from the reading/language GWASMA: rs59197085 (CCDC136/FLNC) and rs5995177 (RBFOX2). There was significant multivariate association of rs5995177 with cortical thickness, driven by effects on left PPG, right MTG, right IFG (both PO and PT), and STG bilaterally. The minor allele, previously associated with reduced reading-language performance, showed negative effects on grey matter thickness. Next, we performed exploratory gene-wide analysis of CCDC136/FLNC and RBFOX2; no other associations surpassed significance thresholds. RBFOX2 encodes an important neuronal regulator of alternative splicing. Thus, the prior reported association of rs5995177 with reading/language performance could potentially be mediated by reduced thickness in associated cortical regions. In future, this hypothesis could be tested using sufficiently large samples containing both neuroimaging data and quantitative reading/language scores from the same individuals.

Abstract

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Abstract

There is evidence that the human cerebellum is involved not only in motor control but also in other cognitive functions. Several studies have shown that language-related activation is lateralized toward the right cerebellar hemisphere in most people, in accordance with leftward cerebral cortical lateralization for language and a general contralaterality of cerebral–cerebellar activations. In terms of behavior, hand use elicits asymmetrical activation in the cerebellum, while hand preference is weakly associated with language lateralization. However, it is not known how, or whether, these functional relations are reflected in anatomy. We investigated volumetric gray matter asymmetries of cerebellar lobules in an MRI data set comprising 2226 subjects. We tested these cerebellar asymmetries for associations with handedness, and for correlations with cerebral cortical anatomical asymmetries of regions important for language or hand motor control, as defined by two different automated image analysis methods and brain atlases, and supplemented with extensive visual quality control. No significant associations of cerebellar asymmetries to handedness were found. Some significant associations of cerebellar lobular asymmetries to cerebral cortical asymmetries were found, but none of these correlations were greater than 0.14, and they were mostly method-/atlas-dependent. On the basis of this large and highly powered study, we conclude that there is no overt structural manifestation of cerebellar functional lateralization and connectivity, in respect of hand motor control or language laterality

Abstract

Neurodevelopmental disorders are defined by highly heritable problems during development and brain growth. Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and intellectual disability (ID) are frequent neurodevelopmental disorders, with common comorbidity among them. Imaging genetics studies on the role of disease-linked genetic variants on brain structure and function have been performed to unravel the etiology of these disorders. Here, we reviewed imaging genetics literature on these disorders attempting to understand the mechanisms of individual disorders and their clinical overlap. For ADHD and ASD, we selected replicated candidate genes implicated through common genetic variants. For ID, which is mainly caused by rare variants, we included genes for relatively frequent forms of ID occurring comorbid with ADHD or ASD. We reviewed case-control studies and studies of risk variants in healthy individuals. Imaging genetics studies for ADHD were retrieved for SLC6A3/DAT1, DRD2, DRD4, NOS1, and SLC6A4/5HTT. For ASD, studies on CNTNAP2, MET, OXTR, and SLC6A4/5HTT were found. For ID, we reviewed the genes FMR1, TSC1 and TSC2, NF1, and MECP2. Alterations in brain volume, activity, and connectivity were observed. Several findings were consistent across studies, implicating, for example, SLC6A4/5HTT in brain activation and functional connectivity related to emotion regulation. However, many studies had small sample sizes, and hypothesis-based, brain region-specific studies were common. Results from available studies confirm that imaging genetics can provide insight into the link between genes, disease-related behavior, and the brain. However, the field is still in its early stages, and conclusions about shared mechanisms cannot yet be drawn.

Abstract

Background

Left-right asymmetry is a fundamental organizing feature of the human brain, and neuro-psychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks post conception, the majority of human fetuses move their right arms more than their left arms, but because nerve fibre tracts are still descending from the forebrain at this stage, spinal-muscular asymmetries are likely to play an important developmental role.
Methods

We used RNA sequencing to measure gene expression levels in the left and right spinal cords, and left and right hindbrains, of 18 post-mortem human embryos aged 4-8 weeks post conception. Genes showing embryonic lateralization were tested for an enrichment of signals in genome-wide association data for schizophrenia.
Results

The left side of the embryonic spinal cord was found to mature faster than the right side. Both sides transitioned from transcriptional profiles associated with cell division and proliferation at earlier stages, to neuronal differentiation and function at later stages, but the two sides were not in synchrony (p = 2.2 E-161). The hindbrain showed a left-right mirrored pattern compared to the spinal cord, consistent with the well-known crossing over of function between these two structures. Genes that showed lateralization in the embryonic spinal cord were enriched for association signals with schizophrenia (p = 4.3 E-05).
Conclusions
These are the earliest-stage left-right differences of human neural development ever reported. Disruption of the lateralised developmental programme may play a role in the genetic susceptibility to schizophrenia.

Abstract

Importance Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. Objectives To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. Design, Setting, and Participants This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1.Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. Main Outcomes and Measures The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. Results Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. Conclusions and Relevance De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

Abstract

It has been observed by several researchers that the Khoisan palate tends to lack a prominent alveolar ridge. A biomechanical model of click production was created to examine if these sounds might be subject to an anatomical bias associated with alveolar ridge size. Results suggest the bias is plausible, taking the form of decreased articulatory effort and improved volume change characteristics; however, further modeling and experimental research is required to solidify the claim.

Abstract

Purpose: Recent proposals suggest that (a) the high dimensionality of speech motor control may be reduced via modular neuromuscular organization that takes advantage of intrinsic biomechanical regions of stability and (b) computational modeling provides a means to study whether and how such modularization works. In this study, the focus is on the larynx, a structure that is fundamental to speech production because of its role in phonation and numerous articulatory functions. Method: A 3-dimensional model of the larynx was created using the ArtiSynth platform (http://www.artisynth.org). This model was used to simulate laryngeal articulatory states, including inspiration, glottal fricative, modal prephonation, plain glottal stop, vocal–ventricular stop, and aryepiglotto– epiglottal stop and fricative. Results: Speech-relevant laryngeal biomechanics is rich with “quantal” or highly stable regions within muscle activation space. Conclusions: Quantal laryngeal biomechanics complement a modular view of speech control and have implications for the articulatory–biomechanical grounding of numerous phonetic and phonological phenomena

Abstract

A commentary on
FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways

by Devanna, P., Middelbeek, J., and Vernes, S. C. (2014). Front. Cell. Neurosci. 8:305. doi: 10.3389/fncel.2014.00305

Abstract

Background: Several nonpsychotic psychiatric disorders in childhood and adolescence can precede the onset of schizophrenia, but the etiology of this relationship remains unclear. We investigated to what extent the association between schizophrenia and psychiatric disorders in childhood is explained by correlated genetic risk factors. Methods: Polygenic risk scores (PRS), reflecting an individual’s genetic risk for schizophrenia, were constructed for 2588 children from the Netherlands Twin Register (NTR) and 6127 from the Avon Longitudinal Study of Parents And Children (ALSPAC). The associations between schizophrenia PRS and measures of anxiety, depression, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder/conduct disorder (ODD/CD) were estimated at age 7, 10, 12/13, and 15 years in the 2 cohorts. Results were then meta-analyzed, and a meta-regression analysis was performed to test differences in effects sizes over, age and disorders. Results: Schizophrenia PRS were associated with childhood and adolescent psychopathology. Meta-regression analysis showed differences in the associations over disorders, with the strongest association with childhood and adolescent depression and a weaker association for ODD/CD at age 7. The associations increased with age and this increase was steepest for ADHD and ODD/CD. Genetic correlations varied between 0.10 and 0.25. Conclusion: By optimally using longitudinal data across diagnoses in a multivariate meta-analysis this study sheds light on the development of childhood disorders into severe adult psychiatric disorders. The results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology as well as with a stronger shared genetic etiology between schizophrenia and adolescent onset psychopathology.

Abstract

This study sought to identify trajectories of DSM-IV based internalizing (INT) and externalizing (EXT) problem scores across childhood and adolescence and to provide insight into the comorbidity by modeling the co-occurrence of INT and EXT trajectories. INT and EXT were measured repeatedly between age 7 and age 15 years in over 7,000 children and analyzed using growth mixture models. Five trajectories were identified for both INT and EXT, including very low, low, decreasing, and increasing trajectories. In addition, an adolescent onset trajectory was identified for INT and a stable high trajectory was identified for EXT. Multinomial regression showed that similar EXT and INT trajectories were associated. However, the adolescent onset INT trajectory was independent of high EXT trajectories, and persisting EXT was mainly associated with decreasing INT. Sex and early life environmental risk factors predicted EXT and, to a lesser extent, INT trajectories. The association between trajectories indicates the need to consider comorbidity when a child presents with INT or EXT disorders, particularly when symptoms start early. This is less necessary when INT symptoms start at adolescence. Future studies should investigate the etiology of co-occurring INT and EXT and the specific treatment needs of these severely affected children.

Abstract

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans

Abstract

The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients. The variant, p.R514H, is located in the forkhead-box DNA-binding domain and is equivalent to the well-studied p.R553H FOXP2 variant that co-segregates with CAS in a large UK family. We present here for the first time a direct comparison of the molecular and clinical consequences of the same mutation affecting the equivalent residue in FOXP1 and FOXP2. Detailed functional characterization of the two variants in cell model systems revealed very similar molecular consequences, including aberrant subcellular localization, disruption of transcription factor activity and deleterious effects on protein interactions. Nonetheless, clinical manifestations were broader and more severe in the three cases carrying the p.R514H FOXP1 variant than in individuals with the p.R553H variant related to CAS, highlighting divergent roles of FOXP2 and FOXP1 in neurodevelopment.

Abstract

Background: Children with a diagnosis of attention-deficit hyperactivity disorder (ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement.

Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N: 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers.

Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 [national tests conducted at age 13–14 years; β = −1.4 (−2.0 to −0.8), P = 2.3 × 10−6), at General Certificate of Secondary Education exams at age 15–16 years (β = −4.0 (−6.1 to −1.9), P = 1.8 × 10−4], reduced odds of sitting Key Stage 5 examinations at age 16–18 years [odds ratio (OR) = 0.90 (0.88 to 0.97), P = 0.001] and lower IQ scores at age 15.5 [β = −0.8 (−1.2 to −0.4), P = 2.4 × 10−4]. Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement [β = −0.09 (−0.10 to −0.06), P = 0.005] and lower maternal IQ [β = −0.6 (−1.2 to −0.1), P = 0.03].

Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects.

Abstract

Background: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and
autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however,
subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD
and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and
cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk.
Methods: Social-communication difficulties (N ≤ 5551, Social and Communication Disorders Checklist, SCDC) and
combined hyperactive-impulsive/inattentive ADHD symptoms (N ≤ 5678, Strengths and Difficulties Questionnaire,
SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary
statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls)
were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between
phenotypes were estimated using genome-wide data.
Results: In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout
development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait rg ≤ 1,
pmin = 3 × 10−4) as those between repeated measures of the same trait (within-trait rg ≤ 0.94, pmin = 7 × 10−4).
Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling
upregulated genes (p-meta = 6.4 × 10−4).
Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles
for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression
R2 = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during
childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores
were linked to genetic risk for disorder.
Conclusions: In the general population, genetic aetiologies between social-communication difficulties and ADHD
symptoms are shared throughout child and adolescent development and may implicate similar biological pathways
that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked
to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional
trait-disorder relationships.

Abstract

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

Abstract

Mendelian randomization (MR) requires strong assumptions about the genetic instruments, of which the most difficult to justify relate to pleiotropy. In a two-sample MR, different methods of analysis are available if we are able to assume, M1: no pleiotropy (fixed effects meta-analysis), M2: that there may be pleiotropy but that the average pleiotropic effect is zero (random effects meta-analysis), and M3: that the average pleiotropic effect is nonzero (MR-Egger). In the latter 2 cases, we also require that the size of the pleiotropy is independent of the size of the effect on the exposure. Selecting one of these models without good reason would run the risk of misrepresenting the evidence for causality. The most conservative strategy would be to use M3 in all analyses as this makes the weakest assumptions, but such an analysis gives much less precise estimates and so should be avoided whenever stronger assumptions are credible. We consider the situation of a two-sample design when we are unsure which of these 3 pleiotropy models is appropriate. The analysis is placed within a Bayesian framework and Bayesian model averaging is used. We demonstrate that even large samples of the scale used in genome-wide meta-analysis may be insufficient to distinguish the pleiotropy models based on the data alone. Our simulations show that Bayesian model averaging provides a reasonable trade-off between bias and precision. Bayesian model averaging is recommended whenever there is uncertainty about the nature of the pleiotropy

Abstract

The CNTNAP2 gene encodes a cell-adhesion molecule that influences the properties of neural networks and the morphology and density of neurons and glial cells. Previous studies have shown association of CNTNAP2 variants with language-related phenotypes in health and disease. Here, we report associations of a common CNTNAP2 polymorphism (rs7794745) with variation in grey matter in a region in the dorsal visual stream. We tried to replicate an earlier study on 314 subjects by Tan and colleagues (2010), but now in a substantially larger group of more than 1700 subjects. Carriers of the T allele showed reduced grey matter volume in left superior occipital gyrus, while we did not replicate associations with grey matter volume in other regions identified by Tan et al (2010). Our work illustrates the importance of independent replication in neuroimaging genetic studies of language-related candidate genes.

Abstract

The brain-derived neurotrophic factor (BDNF) was shown to be involved in spatial memory and spatial strategy preference. A naturally occurring single nucleotide polymorphism of the BDNF gene (Val66Met) affects activity-dependent secretion of BDNF. The current event-related fMRI study on preselected groups of ‘Met’ carriers and homozygotes of the ‘Val’ allele investigated the role of this polymorphism on encoding and retrieval in a virtual navigation task in 37 healthy volunteers. In each trial, participants navigated toward a target object. During encoding, three positional cues (columns) with directional cues (shadows) were available. During retrieval, the invisible target had to be replaced while either two objects without shadows (objects trial) or one object with a shadow (shadow trial) were available. The experiment consisted of blocks, informing participants of which trial type would be most likely to occur during retrieval. We observed no differences between genetic groups in task performance or time to complete the navigation tasks. The imaging results show that Met carriers compared to Val homozygotes activate the left hippocampus more during successful object location memory encoding. The observed effects were independent of non-significant performance differences or volumetric differences in the hippocampus. These results indicate that variations of the BDNF gene affect memory encoding during spatial navigation, suggesting that lower levels of BDNF in the hippocampus results in less efficient spatial memory processing