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Am. J. Psychiat., https://doi.org/10.1176/appi.ajp.20240095
Relationship Between Problematic Alcohol Use and Various Psychiatric Disorders: A Genetically Informed Study
Yeeun Ahn, B.S., Jaehyun Kim, M.D., Kyeongmin Jung, M.S., Dong June Lee, M.S., Jin Young Jung, M.D., M.S., Yewon Eom, Sanghyeon Park, B.S., Jaeyoung Kim, M.S., Hyejin Kim, M.S., Hyeonbin Jo, B.S., Sanghoon Hong, B.S., Kevin S. O’Connell, Ph.D., Ole A. Andreassen, M.D., Ph.D., Woojae Myung, M.D., Ph.D. , and Hong-Hee Won, Ph.D.
Department of Digital Health (Ahn, K. Jung, J.Y. Jung, Park, Jaeyoung Kim, H. Kim, Jo, Hong, Won) and Department of Health Sciences and Technology (Lee), Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea (Ahn, K. Jung, Park, Jaeyoung Kim, Myung); Department of Clinical Medical Sciences (Jaehyun Kim) and Department of Psychiatry (Eom, Myung), Seoul National University College of Medicine, Seoul, South Korea; Department of Medicine, Central Force for National Defense, Republic of Korea Army Personnel Command, Yongin, South Korea (Jaehyun Kim); Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea (Jaehyun Kim); Department of Psychiatry (J.Y. Jung) and Samsung Genome Institute (Won), Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea; Norwegian Center for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo (O’Connell, Andreassen); Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (O’Connell, Andreassen).
Ms. Ahn and Dr. Jaehyun Kim contributed equally to this study.
Dr. Myung and Dr. Won contributed equally to this study.
Send correspondence to Dr. Won and Dr. Myung
Department of Digital Health (Ahn, K. Jung, J.Y. Jung, Park, Jaeyoung Kim, H. Kim, Jo, Hong, Won) and Department of Health Sciences and Technology (Lee), Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea (Ahn, K. Jung, Park, Jaeyoung Kim, Myung); Department of Clinical Medical Sciences (Jaehyun Kim) and Department of Psychiatry (Eom, Myung), Seoul National University College of Medicine, Seoul, South Korea; Department of Medicine, Central Force for National Defense, Republic of Korea Army Personnel Command, Yongin, South Korea (Jaehyun Kim); Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea (Jaehyun Kim); Department of Psychiatry (J.Y. Jung) and Samsung Genome Institute (Won), Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea; Norwegian Center for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo (O’Connell, Andreassen); Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (O’Connell, Andreassen).
Ms. Ahn and Dr. Jaehyun Kim contributed equally to this study.
Dr. Myung and Dr. Won contributed equally to this study.
Send correspondence to Dr. Won and Dr. Myung
Abstract
Objective:
Problematic alcohol use (PAU) adversely affects the clinical course of psychiatric disorders. Genetic studies have suggested that genetic factors underlie the co-occurrence of PAU with psychiatric disorders. This study aimed to elucidate shared genetic architectures, prioritizing genes that disorders may have in common.
Methods:
Using genome-wide association data of PAU including 435,563 samples from people of European ancestry, this study investigated the genetic relationship between PAU and 11 psychiatric disorders using a bivariate causal mixture model (MiXeR). Local genetic correlation and colocalization analyses were conducted to identify the genomic regions significantly associated with PAU and each psychiatric disorder. Postanalysis included the false discovery rate (FDR) and transcriptome-wide association studies (TWASs), as well as summary-data-based Mendelian randomization to prioritize shared genes by integrating brain transcriptome data.
Results:
MiXeR analysis revealed a substantial polygenic overlap (39%–73%) between PAU and psychiatric disorders. Four bivariate genomic regions with high correlations suggest shared causal variants of PAU with major depression and schizophrenia. Within these regions, four and six genes for the PAU–major depression and PAU-schizophrenia pairs, respectively, were mapped by conjunctional FDR analysis. Furthermore, TTC12 and ANKK1 were identified as potential causal genes for PAU and these disorders. The findings were replicated in multi-ancestry analyses of colocalization and TWASs.
Conclusions:
Despite the varying degrees of genetic overlap and directions of shared genetic effect correlations, these results imply the presence of shared genetic factors influencing the comorbidity of PAU and psychiatric disorders. Additionally, TTC12 and ANKK1, located near DRD2, may be causally associated with comorbid conditions.
Problematic alcohol use (PAU) adversely affects the clinical course of psychiatric disorders. Genetic studies have suggested that genetic factors underlie the co-occurrence of PAU with psychiatric disorders. This study aimed to elucidate shared genetic architectures, prioritizing genes that disorders may have in common.
Methods:
Using genome-wide association data of PAU including 435,563 samples from people of European ancestry, this study investigated the genetic relationship between PAU and 11 psychiatric disorders using a bivariate causal mixture model (MiXeR). Local genetic correlation and colocalization analyses were conducted to identify the genomic regions significantly associated with PAU and each psychiatric disorder. Postanalysis included the false discovery rate (FDR) and transcriptome-wide association studies (TWASs), as well as summary-data-based Mendelian randomization to prioritize shared genes by integrating brain transcriptome data.
Results:
MiXeR analysis revealed a substantial polygenic overlap (39%–73%) between PAU and psychiatric disorders. Four bivariate genomic regions with high correlations suggest shared causal variants of PAU with major depression and schizophrenia. Within these regions, four and six genes for the PAU–major depression and PAU-schizophrenia pairs, respectively, were mapped by conjunctional FDR analysis. Furthermore, TTC12 and ANKK1 were identified as potential causal genes for PAU and these disorders. The findings were replicated in multi-ancestry analyses of colocalization and TWASs.
Conclusions:
Despite the varying degrees of genetic overlap and directions of shared genetic effect correlations, these results imply the presence of shared genetic factors influencing the comorbidity of PAU and psychiatric disorders. Additionally, TTC12 and ANKK1, located near DRD2, may be causally associated with comorbid conditions.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-07)
- 국내 연구진
- 의약학 > 유전 및 유전체의학
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