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

Sha, Zhiqiang; Schijven, Dick; Carrión-Castillo, Amaia; Joliot, Marc; Mazoyer, Bernard; Fisher, Simon E.; Crivello, Fabrice; Francks, Clyde

doi:10.1101/2020.06.30.179721

Cited by 19 publications

(35 citation statements)

References 110 publications

(121 reference statements)

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“…Our GWAS analyses revealed no loci that surpassed the standard genome-wide significance threshold p<5e-08, for either horizontal or vertical skew. Other recent GWAS studies [47][48][49], also using UK Biobank data, were able to identify significant loci affecting various regional asymmetries (cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries), which had heritabilities in the same range as the skew measures in the present study. In addition, both skews showed high measurement reliability in twice-scanned individuals.…”

Section: Development Of Global Brain Asymmetrysupporting

confidence: 65%

“…Recent large-scale genome-wide association studies (GWAS) have identified specific loci involved in regional brain asymmetries [47][48][49], and also in left-handedness [50][51][52]. Microtubule-related genes have been particularly implicated by these studies, which is consistent with a role of the cytoskeleton in setting up cellular chirality during embryonic development of the left-right axis of other organs in other species [53][54][55][56].…”

Section: Introductionmentioning

confidence: 60%

“…The most significant gene PLEC encodes plectin, which is a cytoskeletal protein linking the three main components of the cytoskeleton: actin microfilaments, microtubules and intermediate filaments [84]. Cytoskeletal-related genes have also been implicated by other, recent genetic studies of regional structural brain asymmetry and handedness, as well as functional hemispheric language dominance [48,[50][51][52]85]. Cytoskeletal-mediated mechanisms for left-right asymmetry development have been described in invertebrates and frogs [53][54][55][56]85].…”

Section: Development Of Global Brain Asymmetrymentioning

confidence: 99%

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Large-scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

Kong

Postema

Castillo

et al. 2019

Preprint

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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.

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Section: Development Of Global Brain Asymmetrysupporting

confidence: 65%

Section: Introductionmentioning

confidence: 60%

Section: Development Of Global Brain Asymmetrymentioning

confidence: 99%

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Large-scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

Kong

Postema

Castillo

et al. 2019

Preprint

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“…Overall, the top hits of gene-based analysis for HTA have roles in axon morphogenesis and controlling midline crossing. Previous large-scale GWAS for handedness and structural brain asymmetries suggested a role of genes involved in axonogenesis, microtubules and cytoskeleton formation [88][89][90][91] . A smaller GWAS metaanalysis (including the ALSPAC sample) on a quantitative measure of relative hand skill implicated genes with a known role in establishing body asymmetries 55 that also play a role in neurodevelopmental disorders 92 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study and polygenic risk score analysis for hearing measures in children

Schmitz

Abbondanza

Paracchini

2020

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An efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HT) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWAS) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by environmental effects. We analysed HT and HTA in a children population cohort (ALSPAC, n = 6,743, 7.6 years). Better hearing was associated with more advanced cognitive skills and higher socioeconomic status (SES). Mean HTA was negative (−0.28 dB), suggesting a left ear advantage in children but mainly driven by females (−0.48 dB in females v -0.09 dB in males). We performed the first GWAS on HT in children and the very first GWAS on HTA (n = 5,344). Single marker trait association analysis did not yield significant hits. Polygenic risk score (PRS) analysis revealed associations of PRS for schizophrenia with HT, which remained significant after controlling for SES and cognitive skills, and of PRS for autism spectrum disorders (ASD) with HTA. Gene-based analysis for HTA reached genome-wide significance for MCM5, which is implicated in axon morphogenesis. This analysis also highlighted other genes associated with contralateral axon crossing. Some of these genes have previously been reported for ASD. These results further support the hypothesis that pathways distinguishing the left/right axis of the brain (i.e. commissural crossing) contribute to both different types of asymmetries (i.e. HTA) and neurodevelopmental disorders.

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“…In 32,256 adult participants from the general population UK Biobank dataset, we previously found that 42 regional brain asymmetry indexes (AIs) showed significant SNP-based heritabilities ranging from 2.2 to 9.4% 52 . These comprised 28 cortical surface area AIs, 8 cortical thickness AIs, and 6 subcortical volume AIs, where the AI for a given region and individual was calculated as (Left-Right)/((Left+Right)/2) 52 . Multivariate genome-wide association scanning (GWAS) of these AIs implicated genes involved in microtubule-related functions, and genes particularly expressed in the embryonic and fetal brain 52 .…”

Section: Introductionmentioning

confidence: 99%

Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization

Sha

Schijven

Francks

2021

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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 (PRS) 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. PRS 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 PRS was associated with multivariate brain asymmetry after adjusting for sex, ASD PRS r=0.03, p=2.17×10−9, schizophrenia PRS r=0.04, p=2.61×10−11, but the multivariate patterns were mostly distinct for the two PRS, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both PRS 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 risk for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.

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

Cited by 19 publications

References 110 publications

Large-scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

Large-scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew

Genome-wide association study and polygenic risk score analysis for hearing measures in children

Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization

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