Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk
Translational Psychiatry, vol. 12, pp. 420
Abstract
Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multivariate GWAS to tease apart variants associated with problematic alcohol use (ALCP-total) through either a shared risk for externalizing (EXT) or a problematic alcohol use-specific risk (ALCP-specific). SNPs associated with ALCP-specific were primarily related to alcohol metabolism. Genetic correlations showed ALCP-specific was predominantly associated with alcohol use and other forms of psychopathology, but not other forms of substance use. Polygenic scores for ALCP-total were associated with multiple forms of substance use, but polygenic scores for ALCP-specific were only associated with alcohol phenotypes. Polygenic scores for both ALCP-specific and EXT show different patterns of associations with alcohol misuse across development. Our results demonstrate that focusing on both shared and specific risk can better characterize pathways of risk for substance use disorders. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice.
Authors 51
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Peter B. Barr corresponding
SUNY Downstate Health Sciences University · VA NY Harbor Healthcare System
Affiliation as printed
Department of Psychiatry & Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA. peter.barr@downstate.edu
VA New York Harbor Healthcare System, Brooklyn, NY, USA. peter.barr@downstate.edu
Department of Psychiatry & Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Department of Psychiatry, Harvard Medical School, Boston, MA, USA
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
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University of California San Diego · Vanderbilt University Medical Center
Affiliation as printed
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Rutgers, The State University of New Jersey
Affiliation as printed
Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA
Rutgers Addiction Research Center, Rutgers University, Piscataway, NJ, USA
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Affiliation as printed
Department of Economics, Leiden University, Leiden, The Netherlands
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State University of New York · University of Connecticut · SUNY Downstate Health Sciences University · UConn Health
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
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University of Connecticut · Indiana University Indianapolis · Indiana University School of Medicine · UConn Health
Affiliation as printed
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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Washington University in St. Louis · Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
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Rutgers, The State University of New Jersey · Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA
Rutgers Addiction Research Center, Rutgers University, Piscataway, NJ, USA
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
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University of Iowa · Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Affiliation as printed
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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University of Iowa · State University of New York · SUNY Downstate Health Sciences University
Affiliation as printed
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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State University of New York · SUNY Downstate Health Sciences University
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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State University of New York · SUNY Downstate Health Sciences University
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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State University of New York · SUNY Downstate Health Sciences University · Washington University in St. Louis
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
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Washington University in St. Louis
Affiliation as printed
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
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Washington University in St. Louis
Affiliation as printed
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
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Washington University in St. Louis · University of California San Diego
Affiliation as printed
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
University of California, San Diego, La Jolla, California, USA
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Rutgers, The State University of New Jersey · University of California San Diego
Affiliation as printed
University of California, San Diego, La Jolla, California, USA
Department of Genetics, Rutgers University, Piscataway, NJ, USA
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Rutgers, The State University of New Jersey
Affiliation as printed
Department of Genetics, Rutgers University, Piscataway, NJ, USA
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
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Rutgers, The State University of New Jersey
Affiliation as printed
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA
Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
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Rutgers, The State University of New Jersey · University of Pennsylvania
Affiliation as printed
Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
Department of Genetics, Perelman School of Medicine, and the Penn-CHOP Lifespan Brain Institute, University of Pennsylvania, Philadelphia, PA, USA
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University of Pennsylvania · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Genetics, Perelman School of Medicine, and the Penn-CHOP Lifespan Brain Institute, University of Pennsylvania, Philadelphia, PA, USA
Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease Icahn School of Medicine at Mount Sinai, New York, NY, USA
Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease Icahn School of Medicine at Mount Sinai, New York, NY, USA
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Howard University · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Department of Pediatrics, Howard University, Washington, DC, USA
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Howard University · University of Connecticut · UConn Health
Affiliation as printed
Department of Human Genetics, Howard University, Washington, DC, USA
Department of Pediatrics, Howard University, Washington, DC, USA
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
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University of Connecticut · Indiana University Indianapolis · Indiana University School of Medicine · UConn Health
Affiliation as printed
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Center of for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, USA
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Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Center of for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
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Indiana University School of Medicine
Affiliation as printed
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
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University of Iowa · Indiana University School of Medicine
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Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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University of Iowa · University of Connecticut · UConn Health
Affiliation as printed
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
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University of Iowa · State University of New York · University of Connecticut · SUNY Downstate Health Sciences University · UConn Health
Affiliation as printed
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
Department of Psychiatry, University of Iowa, Iowa City, IA, USA
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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State University of New York · SUNY Downstate Health Sciences University
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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State University of New York · SUNY Downstate Health Sciences University
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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State University of New York · SUNY Downstate Health Sciences University
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
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State University of New York · SUNY Downstate Health Sciences University · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Washington University in St. Louis · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease Icahn School of Medicine at Mount Sinai, New York, NY, USA
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
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Washington University in St. Louis
Affiliation as printed
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
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Washington University in St. Louis
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Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
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Rutgers, The State University of New Jersey · Washington University in St. Louis
Affiliation as printed
Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
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Rutgers, The State University of New Jersey · National Institute on Alcohol Abuse and Alcoholism
Affiliation as printed
Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
NIAAA, Bethesda, USA
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National Institute on Alcohol Abuse and Alcoholism
Affiliation as printed
NIAAA, Bethesda, USA
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Emory University · National Institute on Alcohol Abuse and Alcoholism
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NIAAA, Bethesda, USA
Center for Computational and Quantitative Genetics, Emory University, Atlanta, GA, USA
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Emory University · University of California San Diego
Affiliation as printed
Center for Computational and Quantitative Genetics, Emory University, Atlanta, GA, USA
Department of Psychology, Emory University, Atlanta, GA, USA
Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
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University of California San Diego · The University of Texas at Austin
Affiliation as printed
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
Population Research Center, University of Texas at Austin, Austin, TX, USA
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Rutgers, The State University of New Jersey · The University of Texas at Austin
Affiliation as printed
Department of Psychology, University of Texas at Austin, Austin, TX, USA
Population Research Center, University of Texas at Austin, Austin, TX, USA
Rutgers Addiction Research Center, Rutgers University, Piscataway, NJ, USA
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