Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Mol Psychiatry. 2021 Dec;26(12):7652-7660. doi: 10.1038/s41380-021-01204-z. Epub 2021 Jul 1.
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) 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, and schizophrenia r = 0.04, p = 2.61 × 10, 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.
自闭症谱系障碍 (ASD) 和精神分裂症在系统认知风格方面被认为是部分对立的疾病，与男性和女性的平均性别差异相似。大脑的左右不对称是其组织的一个重要方面，表现出性别之间的平均差异，并且在 ASD 和精神分裂症中都可以改变。在这里，我们在来自英国生物库的 32256 名参与者中，绘制了 ASD 和精神分裂症的多基因风险评分与区域性大脑皮质表面积、厚度和皮质下体积测量的不对称性的多元关联。两种疾病的多基因风险呈正相关(r=0.08，p=7.13×10)，且女性比男性更高，这与男性高风险者参与偏倚一致。在调整性别、ASD r=0.03，p=2.17×10 和精神分裂症 r=0.04，p=2.61×10 后，每个多基因风险评分都与大脑不对称的多元关联相关，但多元模式主要是两种多基因风险的区别，两者都与平均性别差异无关。基于元分析功能成像数据的注释表明，两种多基因风险都与语言和执行功能重要区域的不对称性相关，这与表型全基因组关联分析中出现的行为关联一致。总体而言，结果表明，轻微改变的大脑不对称的不同模式可能是 ASD 和精神分裂症多基因风险的功能相关表现，但不能支持其发病机制中的大脑男性化或女性化。
