Bigdeli Tim B, Genovese Giulio, Georgakopoulos Penelope, Meyers Jacquelyn L, Peterson Roseann E, Iyegbe Conrad O, Medeiros Helena, Valderrama Jorge, Achtyes Eric D, Kotov Roman, Stahl Eli A, Abbott Colony, Azevedo Maria Helena, Belliveau Richard A, Bevilacqua Elizabeth, Bromet Evelyn J, Byerley William, Carvalho Celia Barreto, Chapman Sinéad B, DeLisi Lynn E, Dumont Ashley L, O'Dushlaine Colm, Evgrafov Oleg V, Fochtmann Laura J, Gage Diane, Kennedy James L, Kinkead Becky, Macedo Antonio, Moran Jennifer L, Morley Christopher P, Dewan Mantosh J, Nemesh James, Perkins Diana O, Purcell Shaun M, Rakofsky Jeffrey J, Scolnick Edward M, Sklar Brooke M, Sklar Pamela, Smoller Jordan W, Sullivan Patrick F, Macciardi Fabio, Marder Stephen R, Gur Ruben C, Gur Raquel E, Braff David L, Nicolini Humberto, Escamilla Michael A, Vawter Marquis P, Sobell Janet L, Malaspina Dolores, Lehrer Douglas S, Buckley Peter F, Rapaport Mark H, Knowles James A, Fanous Ayman H, Pato Michele T, McCarroll Steven A, Pato Carlos N
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
Institute for Genomic Health, SUNY Downstate Medical Center, Brooklyn, NY, USA.
Mol Psychiatry. 2020 Oct;25(10):2455-2467. doi: 10.1038/s41380-019-0517-y. Epub 2019 Oct 7.
Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R = 0.032; liability R = 0.017; P < 10), Latino (Nagelkerke's R = 0.089; liability R = 0.021; P < 10), and European individuals (Nagelkerke's R = 0.089; liability R = 0.037; P < 10), further highlighting the advantages of incorporating data from diverse human populations.
精神分裂症是一种常见、慢性且使人衰弱的神经精神综合征,影响着全球数千万人。虽然罕见基因变异在精神分裂症的病因中起作用,但目前所解释的大部分遗传易感性存在于常见变异中,这表明在人类从非洲散居之前的变异中,包含了很大一部分可归因于常见变异的遗传力。然而,精神分裂症的常见变异关联研究主要集中在欧洲血统的队列中。我们描述了对6152例非洲裔混血病例和3918例对照,以及1234例拉丁裔病例和3090例对照的全基因组关联研究,这是迄今为止在这些人群中规模最大的此类研究。将非洲裔样本的结果与精神疾病基因组学联盟(PGC)精神分裂症研究的汇总统计数据相结合,产生了7个新的全基因组显著位点,通过纳入拉丁裔样本的结果,我们又确定了另外8个位点。利用连锁不平衡模式中的人群差异,我们在22个先前报道的和4个新的显著位点上实现了更高分辨率的精细定位。多基因风险评分分析显示,基于跨血统荟萃分析结果,非洲裔混血(纳格尔克R值 = 0.032;遗传易感性R值 = 0.017;P < 10)、拉丁裔(纳格尔克R值 = 0.089;遗传易感性R值 = 0.021;P < 10)和欧洲个体(纳格尔克R值 = 0.089;遗传易感性R值 = 0.037;P < 10)的预测得到了改善,进一步突出了纳入不同人群数据的优势。