Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts

Travis T. Mallard, Jeanne E. Savage, Emma C. Johnson, Yuye Huang, Alexis C. Edwards, Jouke J. Hottenga, Andrew D. Grotzinger, Daniel E. Gustavson, Mariela V. Jennings, Andrey Anokhin, Danielle M. Dick, Howard J. Edenberg, John R. Kramer, Dongbing Lai, Jacquelyn L. Meyers, Ashwini K. Pandey, Kathryn Paige Harden, Michel G. Nivard, Eco J.C. de Geus, Dorret I. BoomsmaArpana Agrawal, Lea K. Davis, Toni Kim Clarke, Abraham A. Palmer, Sandra Sanchez-Roige

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Abstract

OBJECTIVE: Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT. METHODS: To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases. RESULTS: The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health. CONCLUSIONS: This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

Original languageEnglish
Pages (from-to)58-70
Number of pages13
JournalAmerican Journal of Psychiatry
Volume179
Issue number1
Early online date14 May 2021
DOIs
Publication statusPublished - Jan 2022

Funding

PRS analyses using UK Biobank data were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. The data sets used for the PheWAS analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding. This research was conducted using the UK Biobank Resource under application numbers 11425 and 16406. The AUDIT data collection in ALSPAC was funded by NIH grant AA018333. 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). For the Netherlands Twin Register, funding was obtained from the Netherlands Organization for Scientific Research (NWO) and the Netherlands Organization for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 400-07-080, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity program 024.001.003, NWO-Groot 480-15-001/674, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007 and 184.033.111), X-Omics 184-034-019; Spi-nozapremie (NWO 56-464-14192), KNAW Academy Professor Award (PAH/6635) and University Research Fellow grant (URF) to Dr. Booms-ma, Amsterdam Public Health research institute (former EMGO1), Neuroscience Amsterdam research institute (former NCA), the European Community’s Fifth and Seventh Framework Program (FP5-LIFE QUALITY-CT-2002-2006, FP7-HEALTH-F4-2007-2013, grant 01254: Ge-nomEUtwin, grant 01413: ENGAGE and grant 602768: ACTION), the European Research Council (ERC Starting 284167, ERC Consolidator 771057, ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), NIH (grants R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951, and 1RC2 MH089995), and the Avera Institute for Human Genetics, Sioux Falls, S.D. Part of the geno-typing and analyses was funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by NWO through grant 2018/EW/ 00408559, BiG Grid, the Dutch e-Science Grid, and SURFsara. Dr. Johnson was supported by funding from NIAAA grant F32AA027435. Ms. Huang, Ms. Jennings, Dr. Palmer, and Dr. Sanchez-Roige were supported by funds from the California Tobacco-Related Disease Research Program (grants 28IR-0070 and T29KT0526). Dr. Edwards was supported by NIAAA grant R01AA027522. Dr. Anokhin was supported by funding from NIH grants K02 DA32573, MH109532, and U10AA008401. Dr. Edenberg and Dr. Kramer were supported by NIAAA grant U10AA008401. Dr. Nivard is supported by NIMH grant R01MH120219, ZonMW grants 849200011 and 531003014 from the Netherlands Organization for Health Research and Development, and a VENI grant awarded by NWO (VI.Veni.191G.030), and he is a Jacobs Foundation Fellow. Dr. Davis obtained support from NIMH grants 1R01MH113362, 1R01MH118233, and 1R56MH120736. Dr. Sanchez-Roige was supported by a NARSAD Young Investigator Award from the Brain and Behavior Foundation (grant 27676). The Collaborative Study on the Genetics of Alcoholism (COGA): principal investigators, B. Porjesz, V. Hesselbrock, T. Foroud; scientific director, A. Agrawal; translational director, D. Dick. The study includes 11 different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, T. Foroud, J. Nurnberger Jr., Y. Liu); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz, J. Meyers, C. Kamarajan, A. Pandey); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal); University of California at San ALSPAC was funded by NIH grant AA018333. 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). For the Netherlands Twin Register, funding was obtained from the Netherlands Organization for Scientific Research (NWO) and the Netherlands Organization for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 400-07-080, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity program 024.001.003, NWO-Groot 480-15-001/674, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007 and 184.033.111), X-Omics 184-034-019; Spinozapremie (NWO 56-464-14192), KNAW Academy Professor Award (PAH/6635) and University Research Fellow grant (URF) to Dr. Boomsma, Amsterdam Public Health research institute (former EMGO1), Neuroscience Amsterdam research institute (former NCA), the European Community’s Fifth and Seventh Framework Program (FP5-LIFE QUALITY-CT-2002-2006, FP7-HEALTH-F4-2007-2013, grant 01254: GenomEUtwin, grant 01413: ENGAGE and grant 602768: ACTION), the European Research Council (ERC Starting 284167, ERC Consolidator 771057, ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), NIH (grants R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951, and 1RC2 MH089995), and the Avera Institute for Human Genetics, Sioux Falls, S.D. Part of the genotyping and analyses was funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by NWO through grant 2018/EW/00408559, BiG Grid, the Dutch e-Science Grid, and SURFsara. PRS analyses using UK Biobank data were carried out on the Genetic Cluster Computer hosted by the Dutch National computing and Networking Services SURFsara. The data sets used for the PheWAS analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding. Dr. Johnson was supported by funding from NIAAA grant F32AA027435. Ms. Huang, Ms. Jennings, Dr. Palmer, and Dr. Sanchez-Roige were supported by funds from the California Tobacco-Related Disease Research Program (grants 28IR-0070 and T29KT0526). Dr. Edwards was supported by NIAAA grant R01AA027522. Dr. Anokhin was supported by funding from NIH grants K02 DA32573, MH109532, and U10AA008401. Dr. Edenberg and Dr. Kramer were supported by NIAAA grant U10AA008401. Dr. Nivard is supported by NIMH grant R01MH120219, ZonMW grants 849200011 and 531003014 from the Netherlands Organization for Health Research and Development, and a VENI grant awarded by NWO (VI.Veni.191G.030), and he is a Jacobs Foundation Fellow. Dr. Davis obtained support from NIMH grants 1R01MH113362, 1R01MH118233, and 1R56MH120736. Dr. Sanchez-Roige was supported by a NARSAD Young Investigator Award from the Brain and Behavior Foundation (grant 27676).

FundersFunder number
Amsterdam Public Health Research Institute
Avera Institute for Human Genetics, Sioux Falls
BBMRI-NL184.033.111, X-Omics 184-034-019, 56-464-14192, 184.021.007
Biobanking and Biomolecular Resources Research Infrastructure
California Tobacco-Related Disease Research Program28IR-0070, T29KT0526, 531003014, 849200011
Dutch National computing and Networking Services SURFsara
ENGAGE602768
European Community’s Fifth and Seventh Framework ProgramFP5-LIFE QUALITY-CT-2002-2006
FP7-HEALTH-F4-2007-201301254, 01413
NBIC/BioAssist/RK2008.024
NWO-Groot480-15-001/674
National Institutes of Health2018/EW/ 00408559, MH109532, K02 DA32573, AA018333
National Institute of Mental Health1RC2 MH089951, 1RC2 MH089995, R01 DK092127-04, DA018673, R01MH120219, U24 MH068457-06, MH081802, R01D0042157-01A1, R01MH58799-03, R56MH120736
National Institute on Drug Abuse
National Institute on Alcohol Abuse and AlcoholismR01AA027522, F32AA027435, U10AA008401
Brain and Behavior Research Foundation27676
National Alliance for Research on Schizophrenia and Depression
Vanderbilt University Medical CenterU01HG006378, R01NS032830, U19HL065962, RC2GM092618, U01HG004798, UL1TR000445, S10RR025141, UL1RR024975, P50GM115305, UL1TR002243, R01HD074711
Engineering Research Centers230374, 284167
European Research Council
Koninklijke Nederlandse Akademie van WetenschappenPAH/6635
ZonMw016-115-035, 463-06-001, 481-08-011, 904-61-090, 904-61-193,480-04-004, 400-05-717, 451-04-034, 024.001.003, 056-32-010, 985-10-002, 400-07-080, 912-10-020
Nederlandse Organisatie voor Wetenschappelijk Onderzoek1R01MH118233, VI.Veni.191G.030, 1R01MH113362, 1R56MH120736
Centre for Medical Systems Biology
Amsterdam Neuroscience

    Keywords

    • Alcohol
    • Alcohol Consumption
    • ALSPAC
    • Genomic Structural Equation Modeling
    • GWAS
    • Substance-Related and Addictive Disorders

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