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The \u2018big five\u2019 personality traits, which include neuroticism, extraversion, agreeableness, conscientiousness and openness, are a widely accepted and influential framework for understanding and describing human personality. Of the big five personality traits, neuroticism has most often been the focus of genetic studies and is linked to various mental illnesses, including depression, anxiety and schizophrenia. Our knowledge of the genetic architecture of the other four personality traits is more limited. Here, utilizing the Million Veteran Program cohort, we conducted a genome-wide association study in individuals of European and African ancestry. Adding other published data, we performed genome-wide association study meta-analysis for each of the five personality traits with sample sizes ranging from 237,390 to 682,688. We identified 208, 14, 3, 2 and 7 independent genome-wide significant loci associated with neuroticism, extraversion, agreeableness, conscientiousness and openness, respectively. These findings represent 62 novel loci for neuroticism, as well as the first genome-wide significant loci discovered for agreeableness. Gene-based association testing revealed 254 genes showing significant association with at least one of the five personality traits. Transcriptome-wide and proteome-wide analysis identified altered expression of genes and proteins such as\n                    <jats:italic>CRHR1, SLC12A5, MAPT<\/jats:italic>\n                    and\n                    <jats:italic>STX4<\/jats:italic>\n                    . Pathway enrichment and drug perturbation analyses identified complex biology underlying human personality traits. We also studied the inter-relationship of personality traits with 1,437 other traits in a phenome-wide genetic correlation analysis, identifying new associations. Mendelian randomization showed positive bidirectional effects between neuroticism and depression and anxiety, while a negative bidirectional effect was observed for agreeableness and these psychiatric traits. This study improves our comprehensive understanding of the genetic architecture underlying personality traits and their relationship to other complex human traits.\n                  <\/jats:p>","DOI":"10.1038\/s41562-024-01951-3","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T06:02:34Z","timestamp":1723442554000},"page":"2235-2249","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology"],"prefix":"10.1038","volume":"8","author":[{"given":"Priya","family":"Gupta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6052-156X","authenticated-orcid":false,"given":"Marco","family":"Galimberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4176-2936","authenticated-orcid":false,"given":"Sarah","family":"Beck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6360-6726","authenticated-orcid":false,"given":"Aliza","family":"Wingo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-6282","authenticated-orcid":false,"given":"Thomas","family":"Wingo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9129-1699","authenticated-orcid":false,"given":"Keyrun","family":"Adhikari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1018-0450","authenticated-orcid":false,"given":"Henry R.","family":"Kranzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"VA Million Veteran Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9564-2871","authenticated-orcid":false,"given":"Murray B.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4067-1859","authenticated-orcid":false,"given":"Joel","family":"Gelernter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8431-9569","authenticated-orcid":false,"given":"Daniel F.","family":"Levey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,12]]},"reference":[{"key":"1951_CR1","unstructured":"John, O. 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J.G. and H.R.K. are holders of US patent 10,900,082 titled: \u2018Genotype-guided dosing of opioid agonists\u2019, issued 26 January 2021. J.G. is paid for editorial work on the journal Complex Psychiatry. The remaining authors declare no competing interests. J.G. is named as an inventor on PCT patent application no. 15\/878,640 entitled \u2018Genotype-guided dosing of opioid agonists\u2019, filed 24 January 2018, and issued on 26 January 2021, as US patent no. 10900082. M.B.S. has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor) and UpToDate (Co-Editor-in-Chief for Psychiatry). No other authors report competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}