アルコール摂取の遺伝学を深く掘り下げる(A Deep Dive Into the Genetics of Alcohol Consumption)

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2024-04-05 カリフォルニア大学サンディエゴ校(UCSD)

カリフォルニア大学サンディエゴ校の研究グループは、直販遺伝子解析企業23andMe社が集めた300万人以上のデータセットを徹底的に調査し、アルコール摂取に影響を与える遺伝子因子と他の疾患との関連性を見出しました。研究は最近、ランセットeBioMedicineに掲載されました。研究は欧州、ラテンアメリカ、アフリカ系アメリカ人という広範な分類に基づいて行われ、アルコール消費量との関連を調査しました。特定のDNAスニップス(SNPs)に着目し、その変異がアルコール行動に影響を与えることを明らかにしました。これらの変異はアルコール使用障害を防ぐ可能性があり、さまざまな健康状態との関連も発見されました。今後の研究では、アルコール保護遺伝子がアルコール以外の条件にも影響を与える可能性があります。

<関連情報>

300万人以上からなる多様なコホートにおけるアルコール使用バリアントのフェノームワイド関連とメンデルランダム化研究 A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals

Mariela V. Jennings,José Jaime Martínez-Magaña,Natasia S. Courchesne-Krak,Renata B. Cupertino,Laura Vilar-Ribó,Sevim B. Bianchi,et al.
eBioMedicine  Published:April 04, 2024
DOI:https://doi.org/10.1016/j.ebiom.2024.105086

アルコール摂取の遺伝学を深く掘り下げる(A Deep Dive Into the Genetics of Alcohol Consumption)

Summary

Background
Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

Methods
We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses.

Findings
The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort.

Interpretation
Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine.

Funding
MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

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