Publications

Abstract

Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.

Abstract

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Abstract

The human cerebral hemispheres show a left–right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4–13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.

Abstract

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here we performed the largest-ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.
Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modelling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.
Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t=2.1, P=0.04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t=2.7, P=0.01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.
Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely under-powered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Abstract

Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. Polygenic risks for the two disorders were positively correlated (r=0.08, p=7.13×10-50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each polygenic risk score was associated with multivariate brain asymmetry after adjusting for sex, ASD r=0.03, p=2.17×10-9, schizophrenia r=0.04, p=2.61×10-11, but the multivariate patterns were mostly distinct for the two polygenic risks, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both polygenic risks were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risks for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.

Abstract

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7—mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

Abstract

Left–right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and it can be altered in cognitive and psychiatric disorders. No mechanism has yet been identified for establishing the human brain’s left–right axis. We performed multivariate genome-wide association scanning of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci associated with different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left–right axis determination in other organs of invertebrates and frogs. Genetic variants associated with brain asymmetry overlapped with those associated with autism, educational attainment and schizophrenia. Comparably large datasets will likely be required in future studies, to replicate and further clarify the associations of microtubule-related genes with variation in brain asymmetry, behavioural and psychiatric traits.

Abstract

To understand the origins of interhemispheric differences and commonalities/coupling in human brain wiring, it is crucial to determine how homologous interregional connectivities of the left and right hemispheres are genetically determined and related. To address this, in the present study, we analyzed human twin and pedigree samples with high-quality diffusion magnetic resonance imaging tractography and estimated the heritability and genetic correlation of homologous left and right white matter (WM) connections. The results showed that the heritability of WM connectivity was similar and coupled between the 2 hemispheres and that the degree of overlap in genetic factors underlying homologous WM connectivity (i.e., interhemispheric genetic correlation) varied substantially across the human brain: from complete overlap to complete nonoverlap. Particularly, the heritability was significantly stronger and the chance of interhemispheric complete overlap in genetic factors was higher in subcortical WM connections than in cortical WM connections. In addition, the heritability and interhemispheric genetic correlations were stronger for long-range connections than for short-range connections. These findings highlight the determinants of the genetics underlying WM connectivity and its interhemispheric relationships, and provide insight into genetic basis of WM connectivity asymmetries in both healthy and disease states.

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

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

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

Objective

Lateralized dysfunction has been suggested in Obsessive-Compulsive Disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of structural brain asymmetry. Here we carried out by far the largest study of brain structural asymmetry in OCD.
Method

We studied a collection of 16 pediatric datasets (501 OCD patients and 439 healthy controls), as well as 30 adult datasets (1777 patients and 1654 controls) from the OCD Working Group within the ENIGMA (Enhancing Neuro-Imaging Genetics through Meta-Analysis) consortium. Asymmetries of the volumes of subcortical structures, and of regional cortical thickness and surface area measures, were assessed based on T1-weighted MRI scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in OCD patients. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.
Results

In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen’s d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, and/or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.
Conclusions

The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.

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

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

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

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

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