Common genetic substrates of alcohol and substance use disorder severity revealed by pleiotropy detection against GWAS catalog in two populations.
Common genetic substrates of alcohol and substance use disorder severity revealed by pleiotropy detection against GWAS catalog in two populations.
复制标题
通过针对两个人群的 GWAS 目录的多效性检测揭示了酒精和物质使用障碍严重程度的常见遗传底物。
DOI：
10.1111/adb.12877
复制
发表时间：
2021
影响因子：
3.4
通讯作者：
Ehlers,CindyL
中科院分区：
文献类型：
--
作者：
Peng,Qian;Wilhelmsen,KirkC;Ehlers,CindyL
酒精和其他物质使用障碍(AUD和SUD)是一种复杂的疾病，被认为具有多基因遗传，通常与其他疾病共存。这种合并症可能部分是通过遗传多效性引起的。对造成这些疾病的大部分变异的特定基因变异的鉴定还没有完成。我们描述了一种灵活的策略，该策略采用变异-特征关联数据库，并确定疾病/海峡的子集是否与研究中的疾病具有潜在的多效性。我们展示了它在两个独立队列中的使用障碍的研究中的使用：美国印第安人(AI)中的酒精、兴奋剂、大麻(CUD)和多物质使用障碍(MSUD)以及墨西哥裔美国人(MA)中的AUD和CUD。使用机器学习方法对GWAS目录中的变体进行处理，我们为每个SUD识别了229到246个AI和153个到160个MA的多效性变体。炎症是AIS中MSUD和AUD最丰富的疾病。在两个队列中，神经功能障碍对CUD的影响最为显著，而在AIS中，对AUD和兴奋剂的影响最为显著。在物质队列之间共享的选定的多效性基因中，与SUD和其他精神疾病有关的多个生物学途径得到了丰富，包括神经营养因子、免疫反应、细胞外基质和昼夜节律调节。共享的多效性基因在SUD中起重要作用的脑区表达显著上调，在食道粘膜中表达下调，在肾上腺中差异表达。这项研究填补了在研究不足的混合种群中检测多效性的空白，并确定了可能成为SUD潜在目标的多效性变异。
Alcohol and other substance use disorders (AUD and SUD) are complex diseases that are postulated to have a polygenic inheritance and are often comorbid with other disorders. The comorbidities may arise partially through genetic pleiotropy. Identification of specific gene variants accounting for large parts of the variance in these disorders has yet to be accomplished. We describe a flexible strategy that takes a variant‐trait association database and determines if a subset of disease/straits are potentially pleiotropic with the disorder under study. We demonstrate its usage in a study of use disorders in two independent cohorts: alcohol, stimulants, cannabis (CUD), and multi‐substance use disorders (MSUD) in American Indians (AI) and AUD and CUD in Mexican Americans (MA). Using a machine learning method with variants in GWAS catalog, we identified 229 to 246 pleiotropic variants for AI and 153 to 160 for MA for each SUD. Inflammation was the most enriched for MSUD and AUD in AIs. Neurological disorder was the most significantly enriched for CUD in both cohorts, and for AUD and stimulants in AIs. Of the select pleiotropic genes shared among substances‐cohorts, multiple biological pathways implicated in SUD and other psychiatric disorders were enriched, including neurotrophic factors, immune responses, extracellular matrix, and circadian regulation. Shared pleiotropic genes were significantly up‐regulated in brain regions playing important roles in SUD, down‐regulated in esophagus mucosa, and differentially regulated in adrenal gland. This study fills a gap for pleiotropy detection in understudied admixed populations and identifies pleiotropic variants that may be potential targets of interest for SUD.