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

/pdf/the-molecular-genetics-of-hand-preference-revisited-2l3f5x9kjq.pdf

The molecular genetics of hand preference revisited

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.

/pdf/the-genetic-architecture-of-structural-left-right-asymmetry-h3x0xdeblq.pdf

The genetic architecture of structural left-right asymmetry of the human brain

Left-right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and can be altered in cognitive and psychiatric disorders1-8. No mechanism has yet been identified for establishing the human brain9s left-right axis9. We performed multivariate genome-wide association scanning (mvGWAS) 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 affecting 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 frogs10-12. Genetic variants affecting brain asymmetry overlapped with those influencing autism, educational attainment and schizophrenia.

/pdf/the-genetic-architecture-of-structural-left-right-asymmetry-3dxed8tydv.pdf

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.

https://www.pnas.org/content/pnas/118/47/e2113095118.full.pdf

Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals.

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it have been reported, which implicated the genes SETDB2, COMT, PCSK6, LRRTM1, SCN11A, AK3, and AR. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we investigated summary statistics from genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=361,194). We also used genome-wide, gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported, nor the whole gene-level for any of the genes listed above. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, for example by continuous measures, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the gene MAP2 in handedness.

/pdf/the-molecular-genetics-of-hand-preference-revisited-4ihhgcup0k.pdf

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.

/pdf/large-scale-phenomic-and-genomic-analysis-of-brain-511n10zmba.pdf

Large-Scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

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, the UK Biobank (N = 39,678), Human Connectome Project (N = 1,113) 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 grey 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 SNP-based heritabilities of 4-13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in GWAS for either skew. There was evidence for a significant genetic correlation (rg=-0.40, p=0.0075) between horizontal brain skew and Autism Spectrum Disorder. 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.

https://www.biorxiv.org/content/biorxiv/early/2020/08/14/756395.full.pdf

Large-scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

No clear monogenic links between left-handedness and situs inversu

The average human brain is characterized by a global left-right asymmetry of shape, including a well-known ‘torque’ on the fronto-occipital axis, and less-studied differences on the dorsal-ventral axis. Torque has been claimed to be human-specific. However, the functional significance and developmental mechanisms underlying the global aspects of brain anatomical asymmetry are unknown. Here we used a registration-based approach with respect to a symmetrical template, to carry out the largest-ever analysis of global brain asymmetry in magnetic resonance imaging data. Three population datasets were used, the UK Biobank (N = 21,389), Human Connectome Project (N = 1,113) and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Variances of this skew on the anterior-occipital and dorsal-ventral axes were largely independent, but both measures were associated with handedness, as well as various regional grey and white matter metrics. Both skew measures also showed heritabilities of 5%-10%, and four potential loci were identified in genome-wide association scanning. Several phenotypic variables related to early life experiences, cognitive functions, or mental health showed associations with the skew measures. These results provide replicable associations of global brain structural asymmetry measures with left-handedness, as well as insights into molecular genetic and early life factors which may contribute to brain asymmetry.

https://www.biorxiv.org/content/biorxiv/early/2019/09/05/756395.full.pdf

Amaia Carrion Castillo

Papers

Large-Scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

Large-scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

No clear monogenic links between left-handedness and situs inversu

Handedness and Other Variables Associated with Human Brain Asymmetrical Skew

The genetics of situs inversus totalis without primary ciliary dyskinesia