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

Zhiqiang Sha,Dick Schijven,Clyde Francks

doi:10.1038/s41380-021-01204-z

Zhiqiang Sha, Dick Schijven + Show 1 more

Open Access

https://doi.org/10.1038/s41380-021-01204-z

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Abstract

Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing vs. empathizing cognitive styles, with resemblances to male vs. 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, and 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 behavioral 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.

Highlights

Autism spectrum disorder (ASD) is a childhood-onset disorder that features deficits in social communication and social interaction, together with restricted or repetitive behavior [1]
Multivariate associations of brain asymmetry with polygenic statistical testing, but rather is designed to assess functional terms with respect to how strongly their meta-analyzed activation patterns correlate with a particular co-activation map derived from an input mask
This analysis was performed for the brain regional asymmetry indexes that showed the strongest loadings with respect to schizophrenia polygenic risk

Summary

INTRODUCTION

Autism spectrum disorder (ASD) is a childhood-onset disorder that features deficits in social communication and social interaction, together with restricted or repetitive behavior [1]. One way to approach the etiologies of these disorders is to study associations of polygenic risk with brain structure and function in general population datasets In this approach, the polygenic risk of a given disorder for each individual within a population cohort is estimated from their own genotypes, in combination with SNP-wise summary statistics from large-scale. We calculated polygenic risk scores for ASD and Polygenic risks and brain asymmetry schizophrenia for each of 32,256 individuals from the UK Biobank brain imaging dataset, by making use of the UK Biobank genotype data in combination with summary statistics from previous genome-wide association scans of ASD [29] and schizophrenia [35]. We used canonical correlation analysis to test the associations of ASD and schizophrenia polygenic risks with multivariate brain structural asymmetry, measured using 42 regional asymmetry indexes.

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