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Grant Details

Grant Number: 5R21CA252916-02 Interpret this number
Primary Investigator: Zhou, Hang
Organization: Yale University
Project Title: Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk
Fiscal Year: 2022


Abstract

Project Summary/Abstract Genetic Causality of Alcohol Intake and Alcohol Use Disorder on Cancer Risk Alcohol use and alcohol use disorder (AUD) are among the leading causes of death and disability worldwide. Ethanol, i.e. beverage alcohol, is mainly oxidized by alcohol dehydrogenases (several ADH genes) to acetaldehyde, which is then detoxified to acetate by aldehyde dehydrogenases (mainly ALDH2). Acetaldehyde and alcoholic beverages are classified as carcinogenic to humans by the International Agency for Research on Cancer. Cumulative epidemiological evidence has shown that alcohol consumption is associated with the development of cancers including upper aerodigestive tract, breast, liver and colorectal cancer; 5.5% of all cancers are attributable to alcohol, totaling 770,000 cases annually. A better understanding of the molecular basis by which alcohol increases cancer risk could lead to improved treatment and preventative strategies. Genome-wide association studies (GWASs) have identified risk genes for alcohol-related traits and cancers, and some genes show pleiotropic effects on both. However, the genetic relationship between alcohol and cancers remains largely unclear. Recently, large GWASs have been conducted on alcohol-related traits and cancers, provided opportunities to answer the above question. The proposed study will take advantage of large scale genetic data in multiple populations to discover genetic risk variants playing roles in both alcohol-related traits (alcohol use and AUD) and alcohol-associated cancers, study the genetic correlations among them, and investigate the genetic causality between alcohol traits and cancers using Mendelian Randomization (MR). Additionally, by integrating summary data regarding large-scale gene expression, eQTL, mQTL, metabolomic QTL and proteomic QTLs into 2-step MR, we aim to identify genes whose expression levels are associated with alcohol-associated cancer variation, identify regulatory and epigenetic markers that mediate the relationship between alcohol and cancers, and identify the relevant pathway mechanisms that involve acetaldehyde and, potentially, other metabolites. This study will help us to understand better the genetic mechanisms that underlie the relationship between alcohol traits and alcohol-associated cancers, with the potential to improve disease prevention and treatment strategies.



Publications

Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits.
Authors: Galimberti M. , Levey D.F. , Deak J.D. , Zhou H. , Stein M.B. , Gelernter J. .
Source: Molecular psychiatry, 2024-04-05; , .
EPub date: 2024-04-05.
PMID: 38580809
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Neurogenetic underpinnings of nicotine use severity: Integrating the brain transcriptomes and GWAS variants via network approaches.
Authors: Yang B.Z. , Xiang B. , Wang T. , Ma S. , Li C.R. .
Source: Psychiatry research, 2024 Apr; 334, p. 115815.
EPub date: 2024-02-28.
PMID: 38422867
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Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.
Authors: Zhou H. , Kember R.L. , Deak J.D. , Xu H. , Toikumo S. , Yuan K. , Lind P.A. , Farajzadeh L. , Wang L. , Hatoum A.S. , et al. .
Source: Nature medicine, 2023 Dec; 29(12), p. 3184-3192.
EPub date: 2023-12-07.
PMID: 38062264
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Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program.
Authors: Cheng Y. , Dao C. , Zhou H. , Li B. , Kember R.L. , Toikumo S. , Zhao H. , Gelernter J. , Kranzler H.R. , Justice A.C. , et al. .
Source: Translational psychiatry, 2023-05-05; 13(1), p. 148.
EPub date: 2023-05-05.
PMID: 37147289
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Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.
Authors: Zhou H. , Kember R.L. , Deak J.D. , Xu H. , Toikumo S. , Yuan K. , Lind P.A. , Farajzadeh L. , Wang L. , Hatoum A.S. , et al. .
Source: medRxiv : the preprint server for health sciences, 2023-01-30; , .
EPub date: 2023-01-30.
PMID: 36747741
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Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder.
Authors: Deak J.D. , Levey D.F. , Wendt F.R. , Zhou H. , Galimberti M. , Kranzler H.R. , Gaziano J.M. , Stein M.B. , Polimanti R. , Gelernter J. , et al. .
Source: JAMA network open, 2022-10-03; 5(10), p. e2238880.
EPub date: 2022-10-03.
PMID: 36301540
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Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.
Authors: Topiwala A. , Taschler B. , Ebmeier K.P. , Smith S. , Zhou H. , Levey D.F. , Codd V. , Samani N.J. , Gelernter J. , Nichols T.E. , et al. .
Source: Molecular psychiatry, 2022 Oct; 27(10), p. 4001-4008.
EPub date: 2022-07-26.
PMID: 35879401
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Alcohol Use and Use Disorder and Cancer Risk: Perspective on Causal Inference.
Authors: Zhou H. , Vasiliou V. .
Source: Complex psychiatry, 2022 Sep; 8(1-2), p. 9-12.
EPub date: 2022-08-09.
PMID: 36601413
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Genome-wide meta-analysis of alcohol use disorder in East Asians.
Authors: Zhou H. , Kalayasiri R. , Sun Y. , Nuñez Y.Z. , Deng H.W. , Chen X.D. , Justice A.C. , Kranzler H.R. , Chang S. , Lu L. , et al. .
Source: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2022 Sep; 47(10), p. 1791-1797.
EPub date: 2022-01-29.
PMID: 35094024
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Associations between moderate alcohol consumption, brain iron, and cognition in UK Biobank participants: Observational and mendelian randomization analyses.
Authors: Topiwala A. , Wang C. , Ebmeier K.P. , Burgess S. , Bell S. , Levey D.F. , Zhou H. , McCracken C. , Roca-Fernández A. , Petersen S.E. , et al. .
Source: PLoS medicine, 2022 Jul; 19(7), p. e1004039.
EPub date: 2022-07-14.
PMID: 35834561
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