{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:58:44Z","timestamp":1792144724501,"version":"4.4.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100010409","name":"Netherlands Organisation for Scientific Research | Nationaal Regieorgaan Praktijkgericht Onderzoek SIA","doi-asserted-by":"publisher","award":["ALWOP.137"],"award-info":[{"award-number":["ALWOP.137"]}],"id":[{"id":"10.13039\/501100010409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010409","name":"Netherlands Organisation for Scientific Research | Nationaal Regieorgaan Praktijkgericht Onderzoek SIA","doi-asserted-by":"publisher","award":["OCENW.KLEIN.071"],"award-info":[{"award-number":["OCENW.KLEIN.071"]}],"id":[{"id":"10.13039\/501100010409","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NA"},{"name":"Funders: Rudolf Magnus Talent Fellowship, Grant reference Number:H150."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neurological and psychiatric disorders, including substance use disorders, share a range of symptoms, which could be the result of shared genetic background. Many genetic loci have been identified for these disorders using genome-wide association studies, but conclusive evidence about cell types wherein these loci are active is lacking. We aimed to uncover implicated brain cell types in neuropsychiatric traits and to assess consistency in results across RNA datasets and methods. We therefore comprehensively employed cell type enrichment methods by integrating single-cell transcriptomic data from mouse brain regions with an unprecedented dataset of 42 human genome-wide association study results of neuropsychiatric, substance use and behavioral\/quantitative brain-related traits (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200912,544,007 individuals). Single-cell transcriptomic datasets from the Karolinska Institute and 10x Genomics were used. Cell type enrichment was determined using Linkage Disequilibrium Score Regression, Multi-marker Analysis of GenoMic Annotation, and Data-driven Expression Prioritized Integration for Complex Traits. We found the largest degree of consistency across methods for implication of pyramidal cells in schizophrenia and cognitive performance. For other phenotypes, such as bipolar disorder, two methods implicated the same cell types, i.e., medium spiny neurons and pyramidal cells. For autism spectrum disorders and anorexia nervosa, no consistency in implicated cell types was observed across methods. We found no evidence for astrocytes being consistently implicated in neuropsychiatric traits. In conclusion, we provide comprehensive evidence for a subset of neuronal cell types being consistently implicated in several, but not all psychiatric disorders, while non-neuronal cell types seem less implicated.\n                  <\/jats:p>","DOI":"10.1038\/s41380-021-01324-6","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:27:32Z","timestamp":1635726452000},"page":"947-955","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4002-9006","authenticated-orcid":false,"given":"M.","family":"Olislagers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3059-5183","authenticated-orcid":false,"given":"K.","family":"Rademaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8994-0661","authenticated-orcid":false,"given":"R. A. H.","family":"Adan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. D.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6439-2774","authenticated-orcid":false,"given":"J. J.","family":"Luykx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,1]]},"reference":[{"key":"1324_CR1","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1037\/0022-006X.70.6.1224","volume":"70","author":"TD Armstrong","year":"2002","unstructured":"Armstrong TD, Costello EJ. Community studies on adolescent substance use, abuse, or dependence and psychiatric comorbidity. J Consult Clin Psychol. 2002;70:1224\u201339.","journal-title":"J Consult Clin Psychol"},{"key":"1324_CR2","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/s00787-006-0535-6","volume":"15","author":"C Couwenbergh","year":"2006","unstructured":"Couwenbergh C, van den Brink W, Zwart K, Vreugdenhil C, van Wijngaarden-Cremers P, van der Gaag RJ. Comorbid psychopathology in adolescents and young adults treated for substance use disorders: a review. Eur Child Adolesc Psychiatry. 2006;15:319\u201328.","journal-title":"Eur Child Adolesc Psychiatry"},{"key":"1324_CR3","unstructured":"Brainstorm C, Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, et al. Analysis of shared heritability in common disorders of the brain. Science. 2018;360:eaap8757."},{"key":"1324_CR4","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/s41576-019-0127-1","volume":"20","author":"V Tam","year":"2019","unstructured":"Tam V, Patel N, Turcotte M, Bosse Y, Pare G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20:467\u201384.","journal-title":"Nat Rev Genet"},{"key":"1324_CR5","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1016\/j.cell.2019.11.020","volume":"179","author":"Cross-Disorder Group of the Psychiatric Genomics Consortium.","year":"2019","unstructured":"Cross-Disorder Group of the Psychiatric Genomics Consortium. Electronic address PMHE, Cross-disorder Group of the Psychiatric Genomics C. genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders. Cell. 2019;179:1469\u201382 e1411.","journal-title":"Cell"},{"key":"1324_CR6","doi-asserted-by":"publisher","first-page":"e1008222","DOI":"10.1371\/journal.pgen.1008222","volume":"15","author":"AI Young","year":"2019","unstructured":"Young AI. Solving the missing heritability problem. PLoS Genet. 2019;15:e1008222.","journal-title":"PLoS Genet"},{"key":"1324_CR7","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3389\/fcvm.2018.00181","volume":"5","author":"H Giral","year":"2018","unstructured":"Giral H, Landmesser U, Kratzer A. Into the wild: GWAS exploration of non-coding RNAs. Front Cardiovasc Med. 2018;5:181.","journal-title":"Front Cardiovasc Med"},{"key":"1324_CR8","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1038\/s41588-018-0129-5","volume":"50","author":"NG Skene","year":"2018","unstructured":"Skene NG, Bryois J, Bakken TE, Breen G, Crowley JJ, Gaspar HA, et al. Genetic identification of brain cell types underlying schizophrenia. Nat Genet. 2018;50:825\u2013833.","journal-title":"Nat Genet"},{"key":"1324_CR9","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1038\/s41588-019-0439-2","volume":"51","author":"HJ Watson","year":"2019","unstructured":"Watson HJ, Yilmaz Z, Thornton LM, Hubel C, Coleman JRI, Gaspar HA, et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet. 2019;51:1207\u20131214.","journal-title":"Nat Genet"},{"key":"1324_CR10","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/s41588-020-0610-9","volume":"52","author":"J Bryois","year":"2020","unstructured":"Bryois J, Skene NG, Hansen TF, Kogelman LJA, Watson HJ, Liu Z, et al. Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson\u2019s disease. Nat Genet. 2020;52:482\u2013493.","journal-title":"Nat Genet"},{"key":"1324_CR11","doi-asserted-by":"crossref","unstructured":"Yurko R, Roeder K, Devlin B, G\u2019Sell M. H-MAGMA, inheriting a shaky statistical foundation, yields excess false positives. Ann Hum Genet. 2021;85:97\u2013100","DOI":"10.1111\/ahg.12412"},{"key":"1324_CR12","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1080\/j.1440-1614.2006.01764.x","volume":"40","author":"SJ Adamson","year":"2006","unstructured":"Adamson SJ, Todd FC, Sellman JD, Huriwai T, Porter J. Coexisting psychiatric disorders in a New Zealand outpatient alcohol and other drug clinical population. Aust N Z J Psychiatry. 2006;40:164\u2013170.","journal-title":"Aust N Z J Psychiatry"},{"key":"1324_CR13","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.jsat.2006.12.031","volume":"34","author":"YF Chan","year":"2008","unstructured":"Chan YF, Dennis ML, Funk RR. Prevalence and comorbidity of major internalizing and externalizing problems among adolescents and adults presenting to substance abuse treatment. J Subst Abus Treat. 2008;34:14\u201324.","journal-title":"J Subst Abus Treat"},{"key":"1324_CR14","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3389\/fgene.2016.00149","volume":"7","author":"CE Carey","year":"2016","unstructured":"Carey CE, Agrawal A, Bucholz KK, Hartz SM, Lynskey MT, Nelson EC, et al. Associations between polygenic risk for psychiatric disorders and substance involvement. Front Genet. 2016;7:149.","journal-title":"Front Genet"},{"key":"1324_CR15","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1038\/ijo.2016.42","volume":"40","author":"N Medic","year":"2016","unstructured":"Medic N, Ziauddeen H, Ersche KD, Farooqi IS, Bullmore ET, Nathan PJ, et al. Increased body mass index is associated with specific regional alterations in brain structure. Int J Obes. 2016;40:1177\u20131182.","journal-title":"Int J Obes"},{"key":"1324_CR16","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1126\/science.aaa1934","volume":"347","author":"A Zeisel","year":"2015","unstructured":"Zeisel A, Munoz-Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A, et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015;347:1138\u20131142.","journal-title":"Science"},{"key":"1324_CR17","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.cell.2016.09.027","volume":"167","author":"G La Manno","year":"2016","unstructured":"La Manno G, Gyllborg D, Codeluppi S, Nishimura K, Salto C, Zeisel A, et al. Molecular diversity of midbrain development in mouse, human, and stem. Cells Cell. 2016;167:566\u2013580 e519.","journal-title":"Cells Cell"},{"key":"1324_CR18","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/nn.4462","volume":"20","author":"RA Romanov","year":"2017","unstructured":"Romanov RA, Zeisel A, Bakker J, Girach F, Hellysaz A, Tomer R, et al. Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nat Neurosci. 2017;20:176\u2013188.","journal-title":"Nat Neurosci"},{"key":"1324_CR19","unstructured":"10X Genomics. Transcriptional profiling of 1.3 million brain cells with the chromium single-cell 3\u2019 solution. 2017."},{"key":"1324_CR20","doi-asserted-by":"publisher","first-page":"16","DOI":"10.3389\/fncom.2016.00016","volume":"10","author":"AA Moustafa","year":"2016","unstructured":"Moustafa AA, Phillips J, Keri S, Misiak B, Frydecka D. On the complexity of brain disorders: a symptom-based approach. Front Comput Neurosci. 2016;10:16.","journal-title":"Front Comput Neurosci"},{"key":"1324_CR21","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/ng.3211","volume":"47","author":"BK Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J, Schizophrenia Working Group of the Psychiatric Genomics C. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015;47:291\u2013295.","journal-title":"Nat Genet"},{"key":"1324_CR22","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/ng.3406","volume":"47","author":"B Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh PR, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236\u20131241.","journal-title":"Nat Genet"},{"key":"1324_CR23","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1038\/ng.3404","volume":"47","author":"HK Finucane","year":"2015","unstructured":"Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015;47:1228\u20131235.","journal-title":"Nat Genet"},{"key":"1324_CR24","doi-asserted-by":"publisher","first-page":"e1004219","DOI":"10.1371\/journal.pcbi.1004219","volume":"11","author":"CA de Leeuw","year":"2015","unstructured":"de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015;11:e1004219.","journal-title":"PLoS Comput Biol"},{"key":"1324_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6890","volume":"6","author":"TH Pers","year":"2015","unstructured":"Pers TH, Karjalainen JM, Chan Y, Westra HJ, Wood AR, Yang J, et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat Commun. 2015;6:5890.","journal-title":"Nat Commun"},{"key":"1324_CR26","doi-asserted-by":"publisher","first-page":"987","DOI":"10.2307\/2529826","volume":"31","author":"MB Brown","year":"1975","unstructured":"Brown MB. A method for combining non-independent, one-sided tests of significance. Biometrics. 1975;31:987\u2013992.","journal-title":"Biometrics"},{"key":"1324_CR27","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1093\/biomet\/48.3-4.419","volume":"48","author":"JP Imhof","year":"1961","unstructured":"Imhof JP. Computing the distribution of quadratic forms in normal variables. Biometrika. 1961;48:419.","journal-title":"Biometrika"},{"key":"1324_CR28","doi-asserted-by":"crossref","unstructured":"de Leeuw C, Sey NYA, Posthuma D, Won H. A response to Yurko et al. H-MAGMA, inheriting a shaky statistical foundation, yields excess false positives. bioRxiv. 2020.","DOI":"10.1101\/2020.09.25.310722"},{"key":"1324_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11181-1","volume":"10","author":"K Watanabe","year":"2019","unstructured":"Watanabe K, Umicevic Mirkov M, de Leeuw CA, van den Heuvel MP, Posthuma D. Genetic mapping of cell-type specificity for complex traits. Nat Commun. 2019;10:3222.","journal-title":"Nat Commun"},{"key":"1324_CR30","doi-asserted-by":"publisher","first-page":"D766","DOI":"10.1093\/nar\/gky955","volume":"47","author":"A Frankish","year":"2019","unstructured":"Frankish A, Diekhans M, Ferreira AM, Johnson R, Jungreis I, Loveland J, et al. GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res. 2019;47:D766\u2013D773.","journal-title":"Nucleic Acids Res"},{"key":"1324_CR31","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"C Genomes Project","year":"2015","unstructured":"Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68\u201374.","journal-title":"Nature"},{"key":"1324_CR32","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/nature10532","volume":"478","author":"D Brawand","year":"2011","unstructured":"Brawand D, Soumillon M, Necsulea A, Julien P, Csardi G, Harrigan P, et al. The evolution of gene expression levels in mammalian organs. Nature. 2011;478:343\u2013348.","journal-title":"Nature"},{"key":"1324_CR33","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1038\/nn.4597","volume":"20","author":"TF Galatro","year":"2017","unstructured":"Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N, Sola PR, et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci. 2017;20:1162\u20131171.","journal-title":"Nat Neurosci"},{"key":"1324_CR34","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.mam.2017.07.002","volume":"59","author":"TS Andrews","year":"2018","unstructured":"Andrews TS, Hemberg M. Identifying cell populations with scRNASeq. Mol Asp Med. 2018;59:114\u201322.","journal-title":"Mol Asp Med"},{"key":"1324_CR35","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1093\/bfgp\/ely001","volume":"18","author":"V Menon","year":"2019","unstructured":"Menon V. Clustering single cells: a review of approaches on high-and low-depth single-cell RNA-seq data. Brief Funct Genom. 2019;18:434.","journal-title":"Brief Funct Genom"},{"key":"1324_CR36","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1016\/j.cell.2016.07.054","volume":"166","author":"K Shekhar","year":"2016","unstructured":"Shekhar K, Lapan SW, Whitney IE, Tran NM, Macosko EZ, Kowalczyk M, et al. Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics. Cell. 2016;166:1308\u20131323 e1330.","journal-title":"Cell"},{"key":"1324_CR37","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1038\/s41588-019-0538-0","volume":"51","author":"CP Fulco","year":"2019","unstructured":"Fulco CP, Nasser J, Jones TR, Munson G, Bergman DT, Subramanian V, et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat Genet. 2019;51:1664\u20131669.","journal-title":"Nat Genet"},{"key":"1324_CR38","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.biopsych.2015.04.012","volume":"79","author":"TF Marton","year":"2016","unstructured":"Marton TF. Sohal VS of mice, men, and microbial opsins: how optogenetics can help hone mouse models of mental illness. Biol Psychiatry. 2016;79:47\u201352.","journal-title":"Biol Psychiatry"},{"key":"1324_CR39","doi-asserted-by":"crossref","unstructured":"Timshel PN, Thompson JJ, Pers TH. Genetic mapping of etiologic brain cell types for obesity. Elife. 2020 21;9:e55851.","DOI":"10.7554\/eLife.55851"},{"key":"1324_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-020-00902-6","volume":"10","author":"Y Wu","year":"2020","unstructured":"Wu Y, Cao H, Baranova A, Huang H, Li S, Cai L, et al. Multi-trait analysis for genome-wide association study of five psychiatric disorders. Transl Psychiatry. 2020;10:209.","journal-title":"Transl Psychiatry"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01324-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01324-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01324-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T04:33:44Z","timestamp":1651206824000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01324-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,1]]},"references-count":40,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["1324"],"URL":"https:\/\/doi.org\/10.1038\/s41380-021-01324-6","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.05.06.442982","asserted-by":"object"}]},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,1]]},"assertion":[{"value":"24 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 September 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All authors declare they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}