Sha Zhiqiang, Warrier Varun, Bethlehem Richard A I, Schultz Laura M, Merikangas Alison, Sun Kevin Y, Gur Ruben C, Gur Raquel E, Shinohara Russell T, Seidlitz Jakob, Almasy Laura, Andreassen Ole A, Alexander-Bloch Aaron F
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
Department of Child and Adolescent Psychiatry and Behavioral Science, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
bioRxiv. 2023 Oct 5:2023.10.05.561040. doi: 10.1101/2023.10.05.561040.
Both psychiatric vulnerability and cortical structure are shaped by the cumulative effect of common genetic variants across the genome. However, the shared genetic underpinnings between psychiatric disorders and brain structural phenotypes, such as thickness and surface area of the cerebral cortex, remains elusive. In this study, we employed pleiotropy-informed conjunctional false discovery rate analysis to investigate shared loci across genome-wide association scans of regional cortical thickness, surface area, and seven psychiatric disorders in approximately 700,000 individuals of European ancestry. Aggregating regional measures, we identified 50 genetic loci shared between psychiatric disorders and surface area, as well as 26 genetic loci shared with cortical thickness. Risk alleles exhibited bidirectional effects on both cortical thickness and surface area, such that some risk alleles for each disorder increased regional brain size while other risk alleles decreased regional brain size. Due to bidirectional effects, in many cases we observed extensive pleiotropy between an imaging phenotype and a psychiatric disorder even in the absence of a significant genetic correlation between them. The impact of genetic risk for psychiatric disorders on regional brain structure did exhibit a consistent pattern across highly comorbid psychiatric disorders, with 80% of the genetic loci shared across multiple disorders displaying consistent directions of effect. Cortical patterning of genetic overlap revealed a hierarchical genetic architecture, with the association cortex and sensorimotor cortex representing two extremes of shared genetic influence on psychiatric disorders and brain structural variation. Integrating multi-scale functional annotations and transcriptomic profiles, we observed that shared genetic loci were enriched in active genomic regions, converged on neurobiological and metabolic pathways, and showed differential expression in postmortem brain tissue from individuals with psychiatric disorders. Cumulatively, these findings provide a significant advance in our understanding of the overlapping polygenic architecture between psychopathology and cortical brain structure.
精神易损性和皮质结构均由全基因组常见基因变异的累积效应塑造而成。然而，精神疾病与大脑结构表型（如大脑皮质厚度和表面积）之间共享的遗传基础仍不明确。在本研究中，我们采用多效性信息联合错误发现率分析，在约70万名欧洲血统个体中，对区域皮质厚度、表面积以及七种精神疾病的全基因组关联扫描结果进行研究，以探寻共享基因座。通过汇总区域测量结果，我们确定了精神疾病与表面积之间共享的50个基因座，以及与皮质厚度共享的26个基因座。风险等位基因对皮质厚度和表面积均呈现双向效应，即每种疾病的某些风险等位基因会增加区域脑容量，而其他风险等位基因则会减小区域脑容量。由于存在双向效应，在许多情况下，即使成像表型与精神疾病之间不存在显著的遗传相关性，我们仍观察到它们之间存在广泛的多效性。精神疾病的遗传风险对区域脑结构的影响在高度共病的精神疾病中确实呈现出一致的模式，80%在多种疾病中共享的基因座显示出一致的效应方向。遗传重叠的皮质模式揭示了一种分层遗传结构，联合皮质和感觉运动皮质代表了对精神疾病和脑结构变异共享遗传影响的两个极端。整合多尺度功能注释和转录组谱，我们观察到共享基因座在活跃基因组区域富集，汇聚于神经生物学和代谢途径，并在精神疾病患者的死后脑组织中表现出差异表达。总体而言，这些发现极大地推进了我们对精神病理学与皮质脑结构之间重叠多基因结构的理解。
