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科学家揭示11种主要精神疾病的遗传结构特征
2022-05-08 16:42

美国科罗拉多大学博尔德分校Andrew D. Grotzinger研究小组在生物行为、功能基因组和分子遗传水平对11种主要精神疾病的遗传结构进行了分析。该项研究成果发表在2022年5月5日出版的《自然-遗传学》上。

研究人员在生物行为、功能基因组和分子遗传分析水平揭示了11种主要精神疾病的遗传结构。研究人员确定了导致疾病之间遗传相关性的四个普遍因素(神经发育、强迫、精神病和内化),并测试这些因素是否充分解释了它们与生物行为特征的遗传相关性。研究人员建立了分层基因组结构方程模型,并用它来鉴别对遗传风险产生不成比例的基因集。这包括在兴奋性和GABA能脑细胞中表达蛋白质截断变异的不耐受基因,这些基因富含具有精神病特征的遗传重叠。

多变量关联分析检测到152个(20个新的)独立位点,这些位点作用于单个因素;并确定了9个位点,这些位点在单因素疾病中表现出异质性。尽管这11种疾病均具有中度至高度的遗传相关性,但该发现表明无论是在生物行为相关性水平还是在个体变异水平,精神疾病的单一遗传风险维度几乎没有效用。

附:英文原文

Title: Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis

Author: Grotzinger, Andrew D., Mallard, Travis T., Akingbuwa, Wonuola A., Ip, Hill F., Adams, Mark J., Lewis, Cathryn M., McIntosh, Andrew M., Grove, Jakob, Dalsgaard, Sren, Lesch, Klaus-Peter, Strom, Nora, Meier, Sandra M., Mattheisen, Manuel, Brglum, Anders D., Mors, Ole, Breen, Gerome, Lee, Phil H., Kendler, Kenneth S., Smoller, Jordan W., Tucker-Drob, Elliot M., Nivard, Michel G.

Issue&Volume: 2022-05-05

Abstract: 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 new) 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. Joint analysis of 11 major psychiatric disorders identifies four broad factor underlying genetic correlations among the disorders. Association analyses detect 152 loci acting on these factors and identify 9 loci that act heterogeneously across disorders.

DOI: 10.1038/s41588-022-01057-4

Source: https://www.nature.com/articles/s41588-022-01057-4

 

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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