{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:52:17Z","timestamp":1791298337394,"version":"4.1.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007937","name":"Peking University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007937","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:p>Coffee or caffeine consumption has been associated with neuropsychiatric disorders, implying a shared etiology. However, whether these associations reflect causality remains largely unknown. To understand the genetic structure of the association between decaffeinated coffee consumption (DCC) and neuropsychiatric traits, we examined the genetic correlation, causality, and shared genetic structure between DCC and neuropsychiatric traits using linkage disequilibrium score regression, bidirectional Mendelian randomization (MR), and genome-wide cross-trait meta-analysis in large GWAS Consortia for coffee consumption (<jats:italic>N<\/jats:italic> = 329,671) and 13 neuropsychiatric traits (sample size ranges from 36,052 to 500,199). We found strong positive genetic correlations between DCC and lifetime cannabis use (LCU; Rg = 0.48, <jats:italic>P<\/jats:italic> = 8.40 \u00d7 10<jats:sup>\u221219<\/jats:sup>), alcohol use disorder identification test (AUDIT) total score (AUDIT_T; Rg = 0.40, <jats:italic>P<\/jats:italic> = 4.63 \u00d7 10<jats:sup>\u221213<\/jats:sup>), AUDIT_C score (alcohol consumption component of the AUDIT; Rg = 0.40, <jats:italic>P<\/jats:italic> = 5.26 \u00d7 10<jats:sup>\u221211<\/jats:sup>), AUDIT_P score (dependence and hazardous-use component of the AUDIT; Rg = 0.28, <jats:italic>P<\/jats:italic> = 1.36 \u00d7 10<jats:sup>\u221205<\/jats:sup>), and strong negative genetic correlations between DCC and neuroticism (Rg = \u22120.15, <jats:italic>P<\/jats:italic> = 7.27 \u00d7 10<jats:sup>\u221205<\/jats:sup>), major depressed diseases (MDD; Rg = \u22120.15, <jats:italic>P<\/jats:italic> = 0.0010), and insomnia (Rg= \u22120.15, <jats:italic>P<\/jats:italic> = 0.0007). In the cross-trait meta-analysis, we identified 6, 5, 1, 1, 2, 31, and 27 shared loci between DCC and Insomnia, LCU, AUDIT_T, AUDIT_C, AUDIT_P, neuroticism, and MDD, respectively, which were mainly enriched in bone marrow, lymph node, cervix, uterine, lung, and thyroid gland tissues, T cell receptor signaling pathway, antigen receptor-mediated signaling pathway, and epigenetic pathways. A large of TWAS-significant associations were identified in tissues that are part of the nervous system, digestive system, and exo-\/endocrine system. Our findings further indicated a causal influence of liability to DCC on LCU and low risk of MDD (odds ratio: 0.90, <jats:italic>P<\/jats:italic> = 9.06 \u00d7 10<jats:sup>\u22125<\/jats:sup> and 1.27, <jats:italic>P<\/jats:italic> = 7.63 \u00d7 10<jats:sup>\u22124<\/jats:sup> respectively). We also observed that AUDIT_T and AUDIT_C were causally related to DCC (odds ratio: 1.83 per 1-SD increase in AUDIT_T, <jats:italic>P<\/jats:italic> = 1.67 \u00d7 10<jats:sup>\u221205<\/jats:sup>, 1.80 per 1-SD increase in AUDIT_C, <jats:italic>P<\/jats:italic> = 5.09 \u00d7 10<jats:sup>\u221204<\/jats:sup>). Meanwhile, insomnia and MDD had a causal negative influence on DCC (OR: 0.91, 95% CI: 0.86\u20130.95, <jats:italic>P<\/jats:italic> = 1.51 \u00d7 10<jats:sup>\u221204<\/jats:sup> for Insomnia; OR: 0.93, 95% CI: 0.89\u20130.99, <jats:italic>P<\/jats:italic> = 6.02 \u00d7 10<jats:sup>\u221204<\/jats:sup> for MDD). These findings provided evidence for the shared genetic basis and causality between DCC and neuropsychiatric diseases, and advance our understanding of the shared genetic mechanisms underlying their associations, as well as assisting with making recommendations for clinical works or health education.<\/jats:p>","DOI":"10.3389\/fpsyt.2022.910432","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T04:59:13Z","timestamp":1657515553000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Shared Genetics and Causality Between Decaffeinated Coffee Consumption and Neuropsychiatric Diseases: A Large-Scale Genome-Wide Cross-Trait Analysis and Mendelian Randomization Analysis"],"prefix":"10.3389","volume":"13","author":[{"given":"Bian","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinpei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep31590","article-title":"Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption","volume":"6","author":"Pirastu","year":"2016","journal-title":"Sci Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1001\/archinternmed.2011.393","article-title":"Coffee, caffeine, and risk of depression among women","volume":"171","author":"Lucas","year":"2011","journal-title":"Arch Intern Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1046\/j.1468-1331.2002.00421.x","article-title":"Does caffeine intake protect from Alzheimer's disease?","volume":"9","author":"Maia","year":"2002","journal-title":"Eur J Neurol."},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1002\/9781119949893","volume-title":"Coffee: Emerging Health Effects and Disease Prevention","author":"Chu","year":"2012"},{"key":"B5","doi-asserted-by":"publisher","first-page":"nzz031","DOI":"10.1093\/cdn\/nzz031.OR29-04-19","article-title":"L-theanine and caffeine improve sustained attention, impulsivity and cognition in children with attention deficit hyperactivity disorders by decreasing mind wandering (OR29-04-19)","volume":"3","author":"Kahathuduwa","year":"2019","journal-title":"Curr Dev Nutr."},{"key":"B6","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1097\/WNF.0000000000000222","article-title":"Effect of excessive coffee consumption on the clinical course of a patient with bipolar disorder: a case report and literature review","volume":"40","author":"Kunitake","year":"2017","journal-title":"Clin Neuropharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1192\/apt.11.6.432","article-title":"Neuropsychiatric effects of caffeine","volume":"11","author":"Winston","year":"2005","journal-title":"Adv Psychiatr Treat."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/ng.3406","article-title":"An atlas of genetic correlations across human diseases and traits","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD Score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1093\/bioinformatics\/btw613","article-title":"LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis","volume":"33","author":"Zheng","year":"2017","journal-title":"Bioinformatics."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.1111\/j.1360-0443.2008.02375.x","article-title":"Genetics of coffee consumption and its stability","volume":"103","author":"Laitala","year":"2008","journal-title":"Addiction."},{"key":"B12","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1375\/twin.12.2.127","article-title":"A genetic analysis of coffee consumption in a sample of Dutch twins","volume":"12","author":"Vink","year":"2009","journal-title":"Twin Res Hum Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.jad.2007.07.001","article-title":"Heritability of bipolar spectrum disorders. 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