Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis.
Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis.
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DOI：
10.1038/s41588-022-01057-4
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发表时间：
2022-05
期刊：
影响因子：
30.8
通讯作者：
Nivard, Michel G.
中科院分区：
文献类型：
--
作者：
Grotzinger, Andrew D.;Mallard, Travis T.;Akingbuwa, Wonuola A.;Ip, Hill F.;Adams, Mark J.;Lewis, Cathryn M.;McIntosh, Andrew M.;Grove, Jakob;Dalsgaard, Soren;Lesch, Klaus-Peter;Strom, Nora;Meier, Sandra M.;Mattheisen, Manuel;Borglum, Anders D.;Mors, Ole;Breen, Gerome;Lee, Phil H.;Kendler, Kenneth S.;Smoller, Jordan W.;Tucker-Drob, Elliot M.;Nivard, Michel G.
我们在生物行为、功能基因组和分子遗传水平上分析了11种主要精神疾病的联合遗传结构。我们确定了四个广泛的因素（神经发育，强迫，精神病，和内化），这些因素之间的遗传相关性的障碍，并测试这些因素是否足以解释其与生物行为特征的遗传相关性。我们引入分层基因组结构方程模型，我们用它来确定基因集，不成比例地贡献遗传风险分担。这包括在兴奋性和GABA能脑细胞中表达的蛋白质截短变异不耐受基因，这些基因在具有精神病特征的疾病中富集遗传重叠。多变量关联分析检测152个（20个新的）独立的基因座，作用于个体因素，并确定9个基因座，在一个因素内的疾病之间的异质性。尽管所有11种疾病都存在中度至高度的遗传相关性，但我们发现，无论是在生物行为相关性水平还是在个体变异水平上，精神疾病的遗传风险的单一维度都没有多大用处。
We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic, and molecular genetic levels of analysis. We identify four broad factors (Neurodevelopmental, Compulsive, Psychotic, and Internalizing) that underlie genetic correlations among the disorders, and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce Stratified Genomic Structural Equation Modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant–intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 novel) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.
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DOI：
10.1038/npp.2017.5
发表时间：
2017-05
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
Ho NF;Holt DJ;Cheung M;Iglesias JE;Goh A;Wang M;Lim JK;de Souza J;Poh JS;See YM;Adcock AR;Wood SJ;Chee MW;Lee J;Zhou J
通讯作者：
Zhou J
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
16.6
作者：
Kranzler, Henry R.;Zhou, Hang;Gelernter, Joel
通讯作者：
Gelernter, Joel