Uncovering genetic mechanisms associated with harmful use of alcohol in admixed Latin Americans.

IF 3.5 2区 生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Edson H B Amaral, Gabriela de S G Britto, Raquel B de São Pedro, Alberto O Moreira, Marília O Scliar, Ricardo Lyra, Natália P Lima, Caroline A Feitosa, Camila A V Figueiredo, Helena M Pitangueira, Thiago Magalhães da Silva, Luydson R S Vasconcelos, Rodrigo F Carmo, Maurício L Barreto, Eduardo Tarazona-Santos, Bernardo L Horta, Ana L Brunialti-Godard, Pablo R S Oliveira
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引用次数: 0

Abstract

Background: Harmful use of alcohol (HUA) refers to drinking patterns that are associated with increased risk of medical complications and adverse social impacts. HUA is a multifactorial condition, involving neurotransmission system alterations, environmental factors, and genetic predisposition. Previous studies have identified numerous genetic variants associated with alcohol-related phenotypes. However, the generalizability of these findings remains limited, as most studies have primarily focused on European and Asian populations, leaving other ethnic groups, such as Latino Americans, underrepresented. Here, we explored the genetic mechanisms underlying HUA in admixed Brazilians. HUA was evaluated in 2,840 individuals using the Alcohol Use Disorder Identification Test (AUDIT). Genetic variations were assessed using a genome-wide genotyping array, followed by genotype imputation. Ancestry patterns were estimated by comparing individual variants with those of reference populations. Association analysis was performed using multivariate logistic regression, and the functional impacts of variants were investigated through in silico analysis. Pathway enrichment and network analyses were conducted to identify potential genetic mechanisms underlying HUA.

Results: Ancestry analysis confirmed the admixed nature of the study population, with lower levels of European ancestry significantly associated (p < 0.05, Mann-Whitney U test) with increased risk of HUA, suggesting potential ancestry-related genetic or socio-environmental factors contributing to alcohol-related behaviors. The genome-wide association study identified a significant association between the variant rs1097611 at 1p33 and HUA p = 4.88 × 10-8, odds ratio [OR] = 1.8, confidence interval [CI] = 1.46-2.23), based on a multivariate logistic regression model assuming additive genetic effects and adjusted for sex and European ancestry. The rs1097611 and other variants at this locus are located in regulatory regions and have been previously associated with differential CYP4B1 expression across multiple tissues. Other suggestive association signals (5 × 10-8 < p < 10- 5) were identified at loci previously implicated in addictive substance use behaviors, including alcohol and/or tobacco consumption, such as 10q21.2 (ARID5B), 5q34-q35.1 (SLIT3), and 10q11.23 (SGMS1). Genome-based pathway enrichment analysis revealed several mechanisms potentially involved in HUA, primarily related to neurobiological processes and neuronal signaling. Finally, network analysis revealed a highly interconnected cluster of nervous system-related pathways, pointing to their potential functional interplay.

Conclusions: This study identifies novel loci, particularly at 1p33 (CYP4B1), and genetic mechanisms potentially involved in HUA in an admixed Latin American population. Studies in diverse ethnic groups are crucial to uncover novel genetic risk variants for HUA and improve its management.

揭示与拉丁美洲混血儿有害使用酒精有关的遗传机制。
背景:有害使用酒精(HUA)是指与医疗并发症风险增加和不良社会影响相关的饮酒模式。HUA是一种多因素疾病,涉及神经传递系统改变、环境因素和遗传易感性。先前的研究已经确定了许多与酒精相关表型相关的遗传变异。然而,这些发现的普遍性仍然有限,因为大多数研究主要集中在欧洲和亚洲人口,而其他种族群体,如拉丁美洲人,代表性不足。在这里,我们探索了混血巴西人HUA的遗传机制。使用酒精使用障碍识别测试(AUDIT)对2840名个体进行HUA评估。使用全基因组基因分型阵列评估遗传变异,然后进行基因型插入。通过比较个体变异与参考群体的变异来估计祖先模式。使用多变量逻辑回归进行关联分析,并通过计算机分析调查变异的功能影响。通过途径富集和网络分析来确定HUA的潜在遗传机制。结果:血统分析证实了研究人群的混合性质,低水平的欧洲血统显著相关(p -8,优势比[OR] = 1.8,置信区间[CI] = 1.46-2.23),基于多变量logistic回归模型,假设加性遗传效应,并调整了性别和欧洲血统。该位点上的rs1097611和其他变异位于调控区域,并且先前与多种组织中CYP4B1的差异表达有关。其他暗示的关联信号(5 × 10-8 < p < 10- 5)在先前涉及成瘾物质使用行为的位点上被发现,包括酒精和/或烟草消费,如10q21.2 (ARID5B), 5q34-q35.1 (SLIT3)和10q11.23 (SGMS1)。基于基因组的通路富集分析揭示了HUA可能涉及的几种机制,主要与神经生物学过程和神经元信号传导有关。最后,网络分析揭示了一个高度互联的神经系统相关通路集群,指出了它们潜在的功能相互作用。结论:本研究确定了新的基因座,特别是在1p33 (CYP4B1),以及在拉丁美洲混合人群中可能涉及HUA的遗传机制。不同族群的研究对于发现HUA的新遗传风险变异和改善其管理至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Genomics
BMC Genomics 生物-生物工程与应用微生物
CiteScore
7.40
自引率
4.50%
发文量
769
审稿时长
6.4 months
期刊介绍: BMC Genomics is an open access, peer-reviewed journal that considers articles on all aspects of genome-scale analysis, functional genomics, and proteomics. BMC Genomics is part of the BMC series which publishes subject-specific journals focused on the needs of individual research communities across all areas of biology and medicine. We offer an efficient, fair and friendly peer review service, and are committed to publishing all sound science, provided that there is some advance in knowledge presented by the work.
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