5. Collaborative Study on the Genetics of Alcoholism: Functional genomics

Author:

Gameiro‐Ros Isabel1ORCID,Popova Dina2,Prytkova Iya1,Pang Zhiping P.23,Liu Yunlong4,Dick Danielle5ORCID,Bucholz Kathleen K.6ORCID,Agrawal Arpana6ORCID,Porjesz Bernice7,Goate Alison M.18,Xuei Xiaoling4,Kamarajan Chella7,Tischfield Jay A.29,Edenberg Howard J.1011,Slesinger Paul A.1,Hart Ronald P.212,

Affiliation:

1. Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai New York New York USA

2. Human Genetics Institute of New Jersey Rutgers University Piscataway New Jersey USA

3. Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School Rutgers University New Brunswick New Jersey USA

4. Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis Indiana USA

5. Rutgers Addiction Research Center, Robert Wood Johnson Medical School Rutgers University Piscataway New Jersey USA

6. Department of Psychiatry Washington University School of Medicine St. Louis Missouri USA

7. Department of Psychiatry and Behavioral Sciences SUNY Downstate Health Sciences University Brooklyn New York USA

8. Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA

9. Department of Genetics Rutgers University Piscataway New Jersey USA

10. Department of Biochemistry and Molecular Biology Indiana University School of Medicine Indianapolis Indiana USA

11. Department of Medical and Molecular Genetics Indiana University Indianapolis Indiana USA

12. Department of Cell Biology and Neuroscience Rutgers University Piscataway New Jersey USA

Abstract

AbstractAlcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome‐wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post‐mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell‐derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.

Funder

National Institute on Alcohol Abuse and Alcoholism

National Institute on Drug Abuse

Publisher

Wiley

Subject

Behavioral Neuroscience,Neurology,Genetics

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