Emma C Johnson1, Manav Kapoor2, Alexander S Hatoum1, Hang Zhou3,4, Renato Polimanti3,4, Frank R Wendt3,4, Raymond K Walters5,6, Dongbing Lai7, Rachel L Kember8,9, Sarah Hartz1, Jacquelyn L Meyers10,11, Roseann E Peterson12, Stephan Ripke5,6,13, Tim B Bigdeli10, Ayman H Fanous10, Carlos N Pato10, Michele T Pato10, Alison M Goate2, Henry R Kranzler8,9, Michael C O'Donovan14, James T R Walters14, Joel Gelernter3,4,15,16, Howard J Edenberg7,17, Arpana Agrawal1. 1. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA. 2. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3. Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, CT, USA. 4. Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA. 5. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 6. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 7. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. 8. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 9. VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA. 10. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA. 11. Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Health Sciences University, Brooklyn, NY, USA. 12. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA. 13. Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany. 14. Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK. 15. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. 16. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA. 17. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
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.
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.
Entities:
Keywords:
Alcohol; genetic overlap; genome wide association study; pleiotropy; schizophrenia
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