Publications

Abstract

Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N= 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein’s function and to be deleterious (rs41298373, P=2.01×10−15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, P=7.54×10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted P=0.025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps<0.05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Abstract

Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7–73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.

Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Abstract

Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the ‘antagonistic pleiotropy’ hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report – https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18–88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.

Abstract

Objective
Determining the genetic basis of speech disorders provides insight into the neurobiology of
human communication. Despite intensive investigation over the past 2 decades, the etiology of
most speech disorders in children remains unexplained. To test the hypothesis that speech
disorders have a genetic etiology, we performed genetic analysis of children with severe speech
disorder, specifically childhood apraxia of speech (CAS).
Methods
Precise phenotyping together with research genome or exome analysis were performed on
children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment
analyses were conducted on high-confidence gene candidates.
Results
Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified
highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1,
DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus)
variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands
and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for
regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated
genes were highly coexpressed in the developing human brain.
Conclusion
We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first
time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous.
Highly penetrant variants implicate shared pathways in broad transcriptional
regulation, highlighting the key role of transcriptional regulation in normal speech development.
CAS is a distinctive, socially debilitating clinical disorder, and understanding its
molecular basis is the first step towards identifying precision medicine approaches.

Abstract

A pivotal question in modern neuroscience is which genes regulate brain circuits that underlie cognitive functions. However, the field is still in its infancy. Here we report an integrated investigation of the high-level language network (i.e., sentence processing network) in the human cerebral cortex, combining regional gene expression profiles, task fMRI, large-scale neuroimaging meta-analysis, and resting-state functional network approaches. We revealed reliable gene expression-functional network correlations using three different network definition strategies, and identified a consensus set of genes related to connectivity within the sentence-processing network. The genes involved showed enrichment for neural development and actin-related functions, as well as association signals with autism, which can involve disrupted language functioning. Our findings help elucidate the molecular basis of the brain’s infrastructure for language. The integrative approach described here will be useful to study other complex cognitive traits.

Abstract

Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.

Abstract

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

Abstract

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Abstract

Background: Generalized Structured Component Analysis (GSCA) is a component-based alternative to traditional covariance-based structural equation modelling. This method has previously been applied to test for association between candidate genes and clinical phenotypes, contrasting with traditional genetic association analyses that adopt univariate testing of many individual single nucleotide polymorphisms (SNPs) with correction for multiple testing.
Methods: We first evaluate the ability of the GSCA method to replicate two previous findings from a genetics association study of developmental language disorders. We then present the results of a simulation study to test the validity of the GSCA method under more restrictive data conditions, using smaller sample sizes and larger numbers of SNPs than have previously been investigated. Finally, we compare GSCA performance against univariate association analysis conducted using PLINK v1.9.
Results: Results from simulations show that power to detect effects depends not just on sample size, but also on the ratio of SNPs with effect to number of SNPs tested within a gene. Inclusion of many SNPs in a model dilutes true effects.
Conclusions: We propose that GSCA is a useful method for replication studies, when candidate SNPs have been identified, but should not be used for exploratory analysis.

Abstract

FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Disruptions of the murine orthologue Foxp2 in mouse pups have been shown to interfere with production of ultrasonic vocalizations (USVs). However, it remains unclear which structures are responsible for these deficits. Here, we show that conditional knockout mice with selective Foxp2 deletions targeting the cerebral cortex, striatum or cerebellum, three key sites of motor control with robust neural gene expression, do not recapture the profile of pup USV deficits observed in mice with global disruptions of this gene. Moreover, we observed that global Foxp2 knockout pups show substantive reductions in USV production as well as an overproduction of short broadband noise “clicks”, which was not present in the brain region-specific knockouts. These data indicate that deficits of Foxp2 expression in the cortex, striatum or cerebellum cannot solely explain the disrupted vocalization behaviours in global Foxp2 knockouts. Our findings raise the possibility that the impact of Foxp2 disruption on USV is mediated at least in part by effects of this gene on the anatomical prerequisites for vocalizing.

Abstract

Importance Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, and Participants In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes and Measures The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions and Relevance These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

Abstract

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

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

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

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

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

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: 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

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.