TY - JOUR
T1 - Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism
AU - Kapoor, Manav
AU - Wang, Jen Chyong
AU - Farris, Sean P.
AU - Liu, Yunlong
AU - McClintick, Jeanette
AU - Gupta, Ishaan
AU - Meyers, Jacquelyn L.
AU - Bertelsen, Sarah
AU - Chao, Michael
AU - Nurnberger, John
AU - Tischfield, Jay
AU - Harari, Oscar
AU - Zeran, Li
AU - Hesselbrock, Victor
AU - Bauer, Lance
AU - Raj, Towfique
AU - Porjesz, Bernice
AU - Agrawal, Arpana
AU - Foroud, Tatiana
AU - Edenberg, Howard J.
AU - Mayfield, R. Dayne
AU - Goate, Alison
N1 - Funding Information:
COGA: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B.P., V.H., H.E., L.B., includes eleven different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J.E., J.N.Jr., T.F.; Y.L.); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B.P.); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A.A.); University of California at San Diego (M. Schuckit); Rutgers University (J.T., A. Brooks); Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA (L. Almasy), Virginia Commonwealth University (D. Dick), Icahn School of Medicine at Mount Sinai (A. Goate), and Howard University (R. Taylor). Other COGA collaborators include: L. Bauer (University of Connecticut); J. McClintick, L. Wetherill, X. Xuei, D. Lai, S. O’Connor, M. Plawecki, S. Lourens (Indiana University); G. Chan (University of Iowa; University of Connecticut); J. Meyers, D. Chorlian, C. Kamarajan, A. Pandey, J. Zhang (SUNY Downstate); J.-C.W., M.K., S.B. (Icahn School of Medicine at Mount Sinai); A. Anokhin, V. McCutcheon, S. Saccone (Washington University); J. Salvatore, F. Aliev, B. Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grande Valley). A. Parsian and H. Chen are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). We are also grateful to the New South Wales Tissue Resource Centre at the University of Sydney for providing human brain samples; the Centre is supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute, and National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA R24AA012725). Mayfield grant support: U01 AA020926 and R01 AA012404. Kapoor grant: R21AA026388. The work was also supported in part by the Integrative Neuroscience Initiative on Alcoholism (INIA)-Neuroimmue consortium (5U24AA025479-02).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank’s alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.
AB - Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank’s alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.
UR - http://www.scopus.com/inward/record.url?scp=85061618848&partnerID=8YFLogxK
U2 - 10.1038/s41398-019-0384-y
DO - 10.1038/s41398-019-0384-y
M3 - Article
C2 - 30765688
AN - SCOPUS:85061618848
SN - 2158-3188
VL - 9
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 89
ER -