{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:47:18Z","timestamp":1790084838781,"version":"4.0.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T00:00:00Z","timestamp":1737331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p><jats:italic>SERINC2<\/jats:italic> has been associated with alcoholism, bipolar disorder and autism, but the comparability and specificity issues of the findings remain unaddressed. The present study aimed to comprehensively analyze various neuropsychiatric disorders pinpoint the most reliable conditions predisposed by <jats:italic>SERINC2<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 2,187 imputed SNPs across <jats:italic>SERINC2<\/jats:italic> were examined in 1,167,439 subjects from 72 independent cohorts with 18 different neuropsychiatric disorders. SNP-disease associations were tested and then meta-analyzed, followed by FDR correction, to identify significant disease-risk SNPs. Finally, functional studies on the differential <jats:italic>SERINC2<\/jats:italic> mRNA expression in brains and the potential regulatory effects of disease-risk alleles on <jats:italic>SERINC2<\/jats:italic> mRNA expression, gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA) and average thickness (TH) were conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In European descent, alcoholism was most significantly associated with <jats:italic>SERINC2<\/jats:italic> variants (245 SNPs with 5.5\u00d710<jats:sup>-8<\/jats:sup>\u2264p \u2264 0.049 and 4.9\u00d710<jats:sup>-5<\/jats:sup>\u2264q \u2264 0.034) that were largely shared across cocaine dependence, marijuana dependence, nicotine dependence, polysubstance dependence, schizophrenia, OCD, and autism (8.2\u00d710<jats:sup>-8<\/jats:sup>\u2264p \u2264 0.050 and 1.9\u00d710<jats:sup>-5<\/jats:sup>\u2264q \u2264 0.049); in Chinese population, bipolar disorder was also significantly associated with <jats:italic>SERINC2<\/jats:italic> variants (10 SNPs: 1.3\u00d710<jats:sup>-4<\/jats:sup>\u2264p \u2264 4.7\u00d710<jats:sup>-4<\/jats:sup> and 0.025\u2264q \u2264 0.031). Furthermore, the disease-risk alleles had highly similar regulatory effects on mRNA expression (8.1\u00d710<jats:sup>-7<\/jats:sup>\u2264p \u2264 0.046), subcortical GMVs (7.0\u00d710<jats:sup>-4<\/jats:sup>\u2264p \u2264 0.048) and cortical TH and SA (1.3\u00d710<jats:sup>-3<\/jats:sup>\u2264p \u2264 0.050) in brains across alcoholism, schizophrenia, OCD and autism. The bipolar disorder-risk alleles had these regulatory effects but with different effect patterns. Finally, <jats:italic>SERINC2<\/jats:italic> mRNA was differentially expressed in several brain regions between alcoholism or schizophrenia and controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>SERINC2<\/jats:italic> is primarily linked to substance use disorders, schizophrenia, OCD, autism and bipolar disorder, not only statistically but also biologically.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2024.1420395","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T12:03:11Z","timestamp":1737374591000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Phenome-wide association studies between SERINC2 and neuropsychiatric disorders"],"prefix":"10.3389","volume":"15","author":[{"given":"Ping","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinqun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawu","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kesheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghua","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zewen","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiang-shan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiren","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingguang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2013.02.006","article-title":"NKAIN1-SERINC2 is a functional, replicable and genome-wide significant risk gene region specific for alcohol dependence in subjects of European descent","volume":"129","author":"Zuo","year":"2013","journal-title":"Drug Alcohol Depend"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/acer.12786","article-title":"A new genomewide association meta-analysis of alcohol dependence","volume":"39","author":"Zuo","year":"2015","journal-title":"Alcohol Clin Exp Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1521-0391.2014.12147.x","article-title":"Genome-wide association discoveries of alcohol dependence","volume":"23","author":"Zuo","year":"2014","journal-title":"Am J Addict"},{"key":"B4","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1097\/FPC.0b013e328362f9f2","article-title":"Rare SERINC2 variants are specific for alcohol dependence in individuals of European descent","volume":"23","author":"Zuo","year":"2013","journal-title":"Pharmacogenet Genomics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/da.23186","article-title":"SERINC2 increases the risk of bipolar disorder in the Chinese population","volume":"38","author":"Yang","year":"2021","journal-title":"Depress Anxiety"},{"key":"B6","doi-asserted-by":"publisher","first-page":"12096","DOI":"10.1038\/s41598-017-12317-3","article-title":"Chromosomal microarray analysis in a cohort of underrepresented population identifies SERINC2 as a novel candidate gene for autism spectrum disorder","volume":"7","author":"Hnoonual","year":"2017","journal-title":"Sci Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M505712200","article-title":"Serinc, an activity-regulated protein family, incorporates serine into membrane lipid synthesis","volume":"280","author":"Inuzuka","year":"2005","journal-title":"J Biol Chem"},{"key":"B8","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/S0896-6273(04)00157-6","article-title":"Lipid rafts mediate chemotropic guidance of nerve growth cones","volume":"42","author":"Guirland","year":"2004","journal-title":"Neuron"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e1000529","DOI":"10.1371\/journal.pgen.1000529","article-title":"A flexible and accurate genotype imputation method for the next generation of genome-wide association studies","volume":"5","author":"Howie","year":"2009","journal-title":"PloS Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1277-4","article-title":"Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism","volume":"132","author":"Zuo","year":"2013","journal-title":"Hum Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.229","article-title":"Genome-wide association study of alcohol dependence implicates KIAA0040 on chromosome 1q","volume":"37","author":"Zuo","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"key":"B13","unstructured":"Storey\n              J\n            \n            \n              Bass\n              A\n            \n            \n              Dabney\n              A\n            \n            \n              Robinson\n              D\n            \n          \n          qvalue: Q-value estimation for false discovery rate control. \n          \n          2023"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653","article-title":"The genotype-tissue expression (GTEx) project","volume":"45","year":"2013","journal-title":"Nat Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.alcohol.2013.07.002","article-title":"Stress-response pathways are altered in the hippocampus of chronic alcoholics","volume":"47","author":"McClintick","year":"2013","journal-title":"Alcohol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2014.70","article-title":"A molecular profile of cocaine abuse includes the differential expression of genes that regulate transcription, chromatin, and dopamine cell phenotype","volume":"39","author":"Bannon","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.30512","article-title":"Transcriptional profiling of subjects from the Iowa adoption studies","author":"Philibert","year":"2007","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001875","article-title":"Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes","volume":"11","author":"Ryan","year":"2006","journal-title":"Mol Psychiatry"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nature09915","article-title":"Modelling schizophrenia using human induced pluripotent stem cells","volume":"473","author":"Brennand","year":"2011","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22647","article-title":"Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia","volume":"89","author":"Barnes","year":"2011","journal-title":"J Neurosci Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2009.18","article-title":"Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function","volume":"14","author":"Maycox","year":"2009","journal-title":"Mol Psychiatry"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e3964","DOI":"10.1371\/journal.pone.0003964","article-title":"The cerebral microvasculature in schizophrenia: a laser capture microdissection study","volume":"3","author":"Harris","year":"2008","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajp.2024.104145","article-title":"Phenome-wide association studies of TXNRD2-COMT-ARVCF cluster pinpoint schizophrenia and bipolar disorder","volume":"98","author":"Guo","year":"2024","journal-title":"Asian J Psychiatr"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214463","article-title":"Abnormal brain structure implicated in stimulant drug addiction","volume":"335","author":"Ersche","year":"2012","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0920-9964(02)00526-1","article-title":"Caudate and putamen volumes in good and poor outcome patients with schizophrenia","volume":"64","author":"Buchsbaum","year":"2003","journal-title":"Schizophr Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/0925-4927(95)02729-H","article-title":"Caudate, putamen, and globus pallidus volume in schizophrenia: a quantitative MRI study","volume":"61","author":"Hokama","year":"1995","journal-title":"Psychiatry Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2014.00957","article-title":"Increased putamen volume in adults with autism spectrum disorder","volume":"8","author":"Sato","year":"2014","journal-title":"Front Hum Neurosci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2005.03.040","article-title":"Striatal volume on magnetic resonance imaging and repetitive behaviors in autism","volume":"58","author":"Hollander","year":"2005","journal-title":"Biol Psychiatry"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1001\/archgenpsychiatry.2010.70","article-title":"Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders","volume":"67","author":"Radua","year":"2010","journal-title":"Arch Gen Psychiatry"},{"key":"B30","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1192\/bjp.bp.108.055046","article-title":"Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder","volume":"195","author":"Radua","year":"2009","journal-title":"Br J Psychiatry"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.2018.62","article-title":"Significant concordance of genetic variation that increases both the risk for obsessive-compulsive disorder and the volumes of the nucleus accumbens and putamen","volume":"213","author":"Hibar","year":"2018","journal-title":"Br J Psychiatry"},{"key":"B32","first-page":"pii:1020","article-title":"Putamen gray matter volumes in neuropsychiatric and neurodegenerative disorders","volume":"3","author":"Luo","year":"2019","journal-title":"World J Psychiatry Ment Health Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/gps.1030","article-title":"Caudate volume measurement in older adults with bipolar disorder","volume":"19","author":"Beyer","year":"2004","journal-title":"Int J Geriatr Psychiatry"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/bdi.12516","article-title":"Amygdala and hippocampus volumes are differently affected by childhood trauma in patients with bipolar disorders and healthy controls","volume":"19","author":"Janiri","year":"2017","journal-title":"Bipolar Disord"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01098-x","article-title":"Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals","volume":"26","author":"McWhinney","year":"2021","journal-title":"Mol Psychiatry"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2022.01.049","article-title":"Pallidal volume reduction and prefrontal-striatal-thalamic functional connectivity disruption in pediatric bipolar disorders","volume":"301","author":"Zhang","year":"2022","journal-title":"J Affect Disord"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2013.00014","article-title":"Alcohol and NMDA receptor: current research and future direction","volume":"6","author":"Chandrasekar","year":"2013","journal-title":"Front Mol Neurosci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2014.187","article-title":"Shared genetic factors influence amygdala volumes and risk for alcoholism","volume":"40","author":"Dager","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.eurpsy.2012.10.002","article-title":"Impaired decision-making and brain shrinkage in alcoholism","volume":"29","author":"Le Berre","year":"2014","journal-title":"Eur Psychiatry"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/uog.13396","article-title":"Severe fetal brain shrinkage following heavy maternal alcohol consumption","volume":"44","author":"Tongsong","year":"2014","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2018.11.030","article-title":"Role of MCP-1 and CCR2 in alcohol neurotoxicity","volume":"139","author":"Zhang","year":"2019","journal-title":"Pharmacol Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s007020170042","article-title":"Increased volume of the nucleus accumbens in schizophrenia","volume":"108","author":"Lauer","year":"2001","journal-title":"J Neural Transm (Vienna)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"3890","DOI":"10.1038\/s41598-023-27448-z","article-title":"A significant, functional and replicable risk KTN1 variant block for schizophrenia","volume":"13","author":"Mao","year":"2023","journal-title":"Sci Rep"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.5152\/alphapsychiatry.2024.241616","article-title":"The role of 3' Regulatory region flanking kinectin 1 gene in schizophrenia","volume":"25","author":"Guo","year":"2024","journal-title":"Alpha Psychiatry"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1023\/a:1025010828304","article-title":"Autism families with a high incidence of alcoholism","volume":"33","author":"Miles","year":"2003","journal-title":"J Autism Dev Disord"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1990.03450190043026","article-title":"Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study","volume":"264","author":"Regier","year":"1990","journal-title":"Jama"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.12740\/PP\/25704","article-title":"Comorbidity of alcohol dependence with other psychiatric disorders","volume":"49","author":"Klimkiewicz","year":"2015","journal-title":"Part I. Epidemiol dual diagnosis]. Psychiatr Pol"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2024.1420395\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T12:03:14Z","timestamp":1737374594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2024.1420395\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,20]]},"references-count":47,"alternative-id":["10.3389\/fpsyt.2024.1420395"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2024.1420395","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,20]]},"article-number":"1420395"}}