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Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder

Published online by Cambridge University Press:  07 July 2021

Emma C. Johnson*
Affiliation:
Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
Manav Kapoor
Affiliation:
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Alexander S. Hatoum
Affiliation:
Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
Hang Zhou
Affiliation:
Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, CT, USA Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
Renato Polimanti
Affiliation:
Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, CT, USA Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
Frank R. Wendt
Affiliation:
Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, CT, USA Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
Raymond K. Walters
Affiliation:
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Dongbing Lai
Affiliation:
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Rachel L. Kember
Affiliation:
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA
Sarah Hartz
Affiliation:
Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
Jacquelyn L. Meyers
Affiliation:
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
Roseann E. Peterson
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
Stephan Ripke
Affiliation:
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
Tim B. Bigdeli
Affiliation:
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
Ayman H. Fanous
Affiliation:
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
Carlos N. Pato
Affiliation:
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
Michele T. Pato
Affiliation:
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
Alison M. Goate
Affiliation:
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Henry R. Kranzler
Affiliation:
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA
Michael C. O'Donovan
Affiliation:
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
James T.R. Walters
Affiliation:
Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
Joel Gelernter
Affiliation:
Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, CT, USA Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA Department of Genetics, Yale University School of Medicine, New Haven, CT, USA Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA
Howard J. Edenberg
Affiliation:
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
Arpana Agrawal
Affiliation:
Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
*Corresponding
Author for correspondence: Emma C. Johnson, E-mail: emma.c.johnson@wustl.edu

Abstract

Background

Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders.

Methods

We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific.

Results

We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001).

Conclusions

Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.

Type
Original Article
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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