Daniel B. Rosoff, Josephin Wagner, Andrew S. Bell, Lucas A. Mavromatis, Jeesun Jung, Falk W. Lohoff
{"title":"A multi-omics Mendelian randomization study identifies new therapeutic targets for alcohol use disorder and problem drinking","authors":"Daniel B. Rosoff, Josephin Wagner, Andrew S. Bell, Lucas A. Mavromatis, Jeesun Jung, Falk W. Lohoff","doi":"10.1038/s41562-024-02040-1","DOIUrl":null,"url":null,"abstract":"<p>Integrating proteomic and transcriptomic data with genetic architectures of problematic alcohol use and alcohol consumption behaviours can advance our understanding and help identify therapeutic targets. We conducted systematic screens using genome-wise association study data from ~3,500 cortical proteins (<i>N</i> = 722) and ~6,100 genes in 8 canonical brain cell types (<i>N</i> = 192) with 4 alcohol-related outcomes (<i>N</i> ≤ 537,349), identifying 217 cortical proteins and 255 cell-type genes associated with these behaviours, with 36 proteins and 37 cell-type genes being new. Although there was limited overlap between proteome and transcriptome targets, downstream neuroimaging revealed shared neurophysiological pathways. Colocalization with independent genome-wise association study data further prioritized 16 proteins, including CAB39L and NRBP1, and 12 cell-type genes, implicating mechanisms such as mTOR signalling. In addition, genes such as <i>SAMHD1</i>, <i>VIPAS39</i>, <i>NUP160</i> and <i>INO80E</i> were identified as having favourable neuropsychiatric profiles. These findings provide insights into the genetic landscapes governing problematic alcohol use and alcohol consumption behaviours, highlighting promising therapeutic targets for future research.</p>","PeriodicalId":19074,"journal":{"name":"Nature Human Behaviour","volume":"34 1","pages":""},"PeriodicalIF":21.4000,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Human Behaviour","FirstCategoryId":"102","ListUrlMain":"https://doi.org/10.1038/s41562-024-02040-1","RegionNum":1,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Integrating proteomic and transcriptomic data with genetic architectures of problematic alcohol use and alcohol consumption behaviours can advance our understanding and help identify therapeutic targets. We conducted systematic screens using genome-wise association study data from ~3,500 cortical proteins (N = 722) and ~6,100 genes in 8 canonical brain cell types (N = 192) with 4 alcohol-related outcomes (N ≤ 537,349), identifying 217 cortical proteins and 255 cell-type genes associated with these behaviours, with 36 proteins and 37 cell-type genes being new. Although there was limited overlap between proteome and transcriptome targets, downstream neuroimaging revealed shared neurophysiological pathways. Colocalization with independent genome-wise association study data further prioritized 16 proteins, including CAB39L and NRBP1, and 12 cell-type genes, implicating mechanisms such as mTOR signalling. In addition, genes such as SAMHD1, VIPAS39, NUP160 and INO80E were identified as having favourable neuropsychiatric profiles. These findings provide insights into the genetic landscapes governing problematic alcohol use and alcohol consumption behaviours, highlighting promising therapeutic targets for future research.
期刊介绍:
Nature Human Behaviour is a journal that focuses on publishing research of outstanding significance into any aspect of human behavior.The research can cover various areas such as psychological, biological, and social bases of human behavior.It also includes the study of origins, development, and disorders related to human behavior.The primary aim of the journal is to increase the visibility of research in the field and enhance its societal reach and impact.