Leger Brittany S, Meredith John J, Ideker Trey, Sanchez-Roige Sandra, Palmer Abraham A
Program in Biomedical Sciences, University of California San Diego, La Jolla, CA, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
bioRxiv. 2024 Mar 1:2024.02.26.582195. doi: 10.1101/2024.02.26.582195.
Genome-wide association studies (GWAS) have identified hundreds of common variants associated with alcohol consumption. In contrast, rare variants have only begun to be studied for their role in alcohol consumption. No studies have examined whether common and rare variants implicate the same genes and molecular networks. To address this knowledge gap, we used publicly available alcohol consumption GWAS summary statistics (GSCAN, N=666,978) and whole exome sequencing data (Genebass, N=393,099) to identify a set of common and rare variants for alcohol consumption. Gene-based analysis of each dataset have implicated 294 (common variants) and 35 (rare variants) genes, including ethanol metabolizing genes and which were identified by both analyses, and , , , and , which were identified only by rare variant analysis, but have been associated with related psychiatric traits. We then used a network colocalization procedure to propagate the common and rare gene sets onto a shared molecular network, revealing significant overlap. The shared network identified gene families that function in alcohol metabolism, including , , , and . 74 of the genes in the network were previously implicated in comorbid psychiatric or substance use disorders, but had not previously been identified for alcohol-related behaviors, including , , , and . Differential gene expression analysis showed enrichment in the liver and several brain regions supporting the role of network genes in alcohol consumption. Thus, genes implicated by common and rare variants identify shared functions relevant to alcohol consumption, which also underlie psychiatric traits and substance use disorders that are comorbid with alcohol use.
全基因组关联研究（GWAS）已经确定了数百个与饮酒相关的常见变异。相比之下，罕见变异在饮酒中的作用才刚刚开始被研究。尚无研究考察常见变异和罕见变异是否涉及相同的基因和分子网络。为了填补这一知识空白，我们使用公开可用的饮酒GWAS汇总统计数据（GSCAN，N = 666,978）和全外显子测序数据（Genebass，N = 393,099）来确定一组饮酒相关的常见和罕见变异。对每个数据集进行的基于基因的分析涉及294个（常见变异）和35个（罕见变异）基因，包括乙醇代谢基因 以及通过两种分析均鉴定出的基因，还有 、 、 和 ，这些基因仅通过罕见变异分析被鉴定出，但已与相关精神特质相关联。然后，我们使用网络共定位程序将常见和罕见基因集传播到一个共享分子网络上，发现了显著的重叠。共享网络确定了在酒精代谢中起作用的基因家族，包括 、 、 和 。该网络中的74个基因先前与共病精神或物质使用障碍有关，但之前未被确定与饮酒相关行为有关，包括 _、 、 和 。差异基因表达分析显示在肝脏和几个脑区存在富集，支持网络基因在饮酒中的作用。因此，由常见和罕见变异所涉及的基因确定了与饮酒相关且与精神特质以及与饮酒共病的物质使用障碍相关的共享功能。
