Federmann Lydia M, Sindermann Lisa, Primus Sabrina, Raimondo Federico, Oexle Konrad, Goltermann Janik, Winkelmann Juliane, Nöthen Markus M, Amunts Katrin, Mühleisen Thomas W, Cichon Sven, Eickhoff Simon B, Hoffstaedter Felix, Dannlowski Udo, Patil Kaustubh R, Forstner Andreas J
Institute of Neuroscience and Medicine, Research Centre Jülich, Jülich, Germany.
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
Transl Psychiatry. 2025 Jul 5;15(1):230. doi: 10.1038/s41398-025-03440-1.
Neuropsychiatric disorders show shared and distinct neurobiological correlates. A cross-disorder genome-wide association study (GWAS) identified 23 highly pleiotropic single-nucleotide polymorphisms (SNPs) that were associated with at least four neuropsychiatric disorders, and 22 SNPs that were associated predominantly with schizophrenia. Exploring their link to brain-related traits might advance understanding their distinct neurobiological processes. Using the UK Biobank data (n = 28,952), this study examined the association of both a genetic risk score (GRS) for highly pleiotropic SNPs (PleioPsych-GRS), and a GRS for predominantly schizophrenia-associated SNPs (SCZ-GRS) with 154 measures of subcortical volume, cortical thickness, and surface area as well as 12 outcomes related to mental health. To generate further insights at the individual SNP level, the association between SNPs and brain structure was examined using GWAS summary statistics. The PleioPsych-GRS showed no significant association with brain structure after correction for multiple testing. The SCZ-GRS showed a significant association with an increased surface area of the lateral orbitofrontal region, and an increased volume of the putamen, among others. The PleioPsych-GRS and the SCZ-GRS were associated with eight and four outcomes related to mental health, respectively. Two highly pleiotropic and 10 SCZ-associated SNPs were associated with several structural brain phenotypes. Taken together, these findings indicated that GRSs of highly pleiotropic SNPs and predominantly schizophrenia-associated SNPs have partly distinct associations with brain structure and outcomes related to mental health. Thus, investigating schizophrenia-specific and pleiotropic variants may improve our understanding of the neurobiology of neuropsychiatric disorders.
神经精神疾病显示出共同且独特的神经生物学关联。一项跨疾病全基因组关联研究（GWAS）确定了23个高度多效性单核苷酸多态性（SNP），这些多态性与至少四种神经精神疾病相关，还有22个主要与精神分裂症相关的SNP。探索它们与脑相关特征的联系可能会促进对其独特神经生物学过程的理解。本研究使用英国生物银行数据（n = 28,952），检验了高度多效性SNP的遗传风险评分（PleioPsych-GRS）以及主要与精神分裂症相关的SNP的遗传风险评分（SCZ-GRS）与154项皮质下体积、皮质厚度和表面积测量指标以及12项心理健康相关结局之间的关联。为了在个体SNP水平上获得进一步见解，使用GWAS汇总统计数据检验了SNP与脑结构之间的关联。经多重检验校正后，PleioPsych-GRS与脑结构无显著关联。SCZ-GRS与外侧眶额区域表面积增加以及壳核体积增加等显著相关。PleioPsych-GRS和SCZ-GRS分别与八项和四项心理健康相关结局相关。两个高度多效性SNP和10个与精神分裂症相关的SNP与几种脑结构表型相关。综上所述，这些发现表明，高度多效性SNP和主要与精神分裂症相关的SNP的遗传风险评分与脑结构和心理健康相关结局存在部分不同的关联。因此，研究精神分裂症特异性和多效性变异可能会增进我们对神经精神疾病神经生物学的理解。
