Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Renaissance Computing Institute, University of North Carolina, Chapel Hill, NC, 27517, USA.
Transl Psychiatry. 2019 Feb 4;9(1):71. doi: 10.1038/s41398-019-0397-6.
A limited number of genetic variants have been identified in traditional GWAS as risk or protective factors for alcohol use disorders (AUD) and related phenotypes. We herein report whole-genome association and rare-variant analyses on AUD traits in American Indians (AI) and European Americans (EA). We evaluated 742 AIs and 1711 EAs using low-coverage whole-genome sequencing. Phenotypes included: (1) a metric based on the occurrence of 36 alcohol-related life events that reflect AUD severity; (2) two alcohol-induced affective symptoms that accompany severe AUDs. We identified two new loci for alcohol-related life events with converging evidence from both cohorts: rare variants of K channel gene KCNK2, and rare missense and splice-site variants in pro-inflammatory mediator gene PDE4C. A NAF1-FSTL5 intergenic variant and an FSTL5 variant were respectively associated with alcohol-related life events in AI and EA. PRKG2 of serine/threonine protein kinase family, and rare variants in interleukin subunit gene EBI3 (IL-27B) were uniquely associated with alcohol-induced affective symptoms in AI. LncRNA LINC02347 on 12q24.32 was uniquely associated with alcohol-induced depression in EA. The top GWAS findings were primarily rare/low-frequency variants in AI, and common variants in EA. Adrenal gland was the most enriched in tissue-specific gene expression analysis for alcohol-related life events, and nucleus accumbens was the most enriched for alcohol-induced affective states in AI. Prefrontal cortex was the most enriched in EA for both traits. These studies suggest that whole-genome sequencing can identify novel, especially uncommon, variants associated with severe AUD phenotypes although the findings may be population specific.
已经在传统的 GWAS 中确定了少数遗传变异，这些变异是酒精使用障碍（AUD）和相关表型的风险或保护因素。本文报告了全基因组关联和罕见变异分析，研究对象为美洲印第安人（AI）和欧洲裔美国人（EA）的 AUD 特征。我们使用低覆盖率全基因组测序评估了 742 名 AI 和 1711 名 EA。表型包括：（1）基于 36 个与酒精相关的生活事件发生的指标，反映 AUD 的严重程度；（2）两种伴随严重 AUD 的酒精引起的情感症状。我们确定了两个与酒精相关的生活事件的新位点，两个队列的证据都有收敛：钾通道基因 KCNK2 的稀有变异，以及促炎介质基因 PDE4C 的罕见错义和剪接位点变异。NAF1-FSTL5 基因间变异和 FSTL5 变异分别与 AI 和 EA 中的酒精相关生活事件相关。丝氨酸/苏氨酸蛋白激酶家族的 PRKG2 和白细胞介素亚基基因 EBI3（IL-27B）的稀有变异与 AI 中的酒精引起的情感症状有关。12q24.32 上的 lncRNA LINC02347 与 EA 中的酒精引起的抑郁有关。全基因组关联研究的主要发现是 AI 中的罕见/低频变异，以及 EA 中的常见变异。在与酒精相关的生活事件的组织特异性基因表达分析中，肾上腺是最丰富的，而在 AI 中，伏隔核是最丰富的与酒精引起的情感状态相关的。前额叶皮层在 EA 中对这两种特征都是最丰富的。这些研究表明，全基因组测序可以识别与严重 AUD 表型相关的新型、特别是罕见的变异，尽管这些发现可能是特定于人群的。
