A high-resolution PheWAS approach to alcohol-related polygenic risk scores reveals mechanistic influences of alcohol reinforcing value and drinking motives.

IF 2.1 4区 医学 Q3 SUBSTANCE ABUSE Alcohol and alcoholism Pub Date : 2024-01-17 DOI:10.1093/alcalc/agad093
Wei Q Deng, Kyla Belisario, Joshua C Gray, Emily E Levitt, James MacKillop
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Abstract

Aims: This study uses a high-resolution phenome-wide approach to evaluate the motivational mechanisms of polygenic risk scores (PRSs) that have been robustly associated with coarse alcohol phenotypes in large-scale studies.

Methods: In a community-based sample of 1534 Europeans, we examined genome-wide PRSs for the Alcohol Use Disorders Identification Test (AUDIT), drinks per week, alcohol use disorder (AUD), problematic alcohol use (PAU), and general addiction, in relation to 42 curated phenotypes. The curated phenotypes were in seven categories: alcohol consumption, alcohol reinforcing value, drinking motives, other addictive behaviors, commonly comorbid psychiatric syndromes, impulsivity, and personality traits.

Results: The PRS for each alcohol phenotype was validated via its within-sample association with the corresponding phenotype (adjusted R2s = 0.35-1.68%, Ps = 0.012-3.6 × 10-7) with the exception of AUD. All PRSs were positively associated with alcohol reinforcing value and drinking motives, with the strongest effects from AUDIT-consumption (adjusted R2s = 0.45-1.33%, Ps = 0.006-3.6 × 10-5) and drinks per week PRSs (adjusted R2s = 0.52-2.28%, Ps = 0.004-6.6 × 10-9). Furthermore, the PAU and drinks per week PRSs were positively associated with adverse childhood experiences (adjusted R2s = 0.6-0.7%, Ps = 0.0001-4.8 × 10-4).

Conclusions: These results implicate alcohol reinforcing value and drinking motives as genetically-influenced mechanisms using PRSs for the first time. The findings also highlight the value of dissecting genetic influence on alcohol involvement through diverse phenotypic risk pathways but also the need for future studies with both phenotypic richness and larger samples.

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对酒精相关多基因风险评分采用高分辨率 PheWAS 方法,揭示了酒精强化价值和饮酒动机的机理影响。
目的:本研究采用高分辨率全表型方法评估多基因风险评分(PRSs)的动机机制,在大规模研究中,多基因风险评分与粗略酒精表型密切相关:在 1534 名欧洲人的社区样本中,我们研究了酒精使用障碍鉴定测试 (AUDIT)、每周饮酒量、酒精使用障碍 (AUD)、问题酒精使用 (PAU) 和一般成瘾的全基因组 PRSs 与 42 个已设定表型的关系。这些表型分为七类:饮酒量、酒精强化价值、饮酒动机、其他成瘾行为、常见合并精神病综合征、冲动性和人格特质:除 AUD 外,每个酒精表型的 PRS 均通过样本内与相应表型的关联得到验证(调整后 R2s = 0.35-1.68%,Ps = 0.012-3.6 × 10-7)。所有 PRS 均与酒精强化价值和饮酒动机呈正相关,其中 AUDIT 消费(调整后 R2s = 0.45-1.33%,Ps = 0.006-3.6 × 10-5)和每周饮酒 PRS(调整后 R2s = 0.52-2.28%,Ps = 0.004-6.6 × 10-9)的影响最强。此外,PAU 和每周饮酒量 PRS 与不良童年经历呈正相关(调整后 R2s = 0.6-0.7%, Ps = 0.0001-4.8 × 10-4):这些结果首次利用PRSs将酒精强化价值和饮酒动机暗示为受基因影响的机制。研究结果还强调了通过不同的表型风险途径剖析遗传对酒精参与的影响的价值,同时也强调了未来研究表型丰富和样本量更大的必要性。
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来源期刊
Alcohol and alcoholism
Alcohol and alcoholism 医学-药物滥用
CiteScore
4.70
自引率
3.60%
发文量
62
审稿时长
4-8 weeks
期刊介绍: About the Journal Alcohol and Alcoholism publishes papers on the biomedical, psychological, and sociological aspects of alcoholism and alcohol research, provided that they make a new and significant contribution to knowledge in the field. Papers include new results obtained experimentally, descriptions of new experimental (including clinical) methods of importance to the field of alcohol research and treatment, or new interpretations of existing results. Theoretical contributions are considered equally with papers dealing with experimental work provided that such theoretical contributions are not of a largely speculative or philosophical nature.
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