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With the novel approach of combined health care registries and self-report measures related to depression, the authors aimed to identify the impact of polygenic risk scores (PRS) for major depression on self report measures and a diagnosis of depression across diagnostic thresholds. The study sample comprised participants from the Norwegian Mother, Father and Child Cohort Study with linked information of depression diagnoses during 2006\u20132022 from health registries. Linear and logistic models were used to estimate the associations between PRS for major depression and self-reported measures related to depression (Symptom Checklist- 5, Satisfaction With Life Scale, Rosenberg Self-Esteem Scale), and a diagnosis of depression. Analyses were performed in groups stratified by level of depression severity defined by registrations in primary and specialist health care. Among the 105 623 individuals included in the study, mean (SD) age was 33.9 (5.3) and 58.5% were female. The associations between PRS for major depression and Rosenberg Self-Esteem Scale were more prominent in individuals with a history of inpatient status compared to outpatient status (\u03b2\u2009=\u20090.095, cluster robust 95% CI 0.029\u20130.162;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.005) and status of primary care (\u03b2\u2009=\u20090.098, cluster robust 95% CI 0.035\u20130.160;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.002). PRS for major depression were associated with a diagnosis of depression in all groups of depression severity, with highest effect sizes for more severe types (history of inpatient status: OR\u2009=\u20091.85, cluster robust 95% CI 1.75\u20131.94;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01). The results provide new knowledge of how PRS for major depression vary with depression severity.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03243-2","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T11:00:32Z","timestamp":1758106832000},"page":"1325-1332","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Associations of polygenic risk scores for major depression and depression severity: an investigation of 105 623 individuals with 16 years follow-up"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9141-1857","authenticated-orcid":false,"given":"Marit","family":"Haram","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Jangmo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Jaholkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00eblle","family":"Pasman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4161-2199","authenticated-orcid":false,"given":"Joeri","family":"Meijsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Shorter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-157X","authenticated-orcid":false,"given":"Elizabeth C.","family":"Corfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6427-2625","authenticated-orcid":false,"given":"Oleksandr","family":"Frei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4653-0034","authenticated-orcid":false,"given":"Ted","family":"Reichborn-Kjennerud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3097-1014","authenticated-orcid":false,"given":"Alfonso","family":"Buil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-3654","authenticated-orcid":false,"given":"Yi","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1829-0766","authenticated-orcid":false,"given":"Thomas","family":"Werge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6619-873X","authenticated-orcid":false,"given":"Patrick","family":"Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-3568","authenticated-orcid":false,"given":"Ole A.","family":"Andreassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7495-5545","authenticated-orcid":false,"given":"Martin","family":"Tesli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"3243_CR1","doi-asserted-by":"publisher","first-page":"e39","DOI":"10.1016\/j.amepre.2020.03.021","volume":"59","author":"J Tam","year":"2020","unstructured":"Tam J, Mezuk B, Zivin K, Meza R. 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PFS is a consultant and shareholder of Neumora Therapeutics. OF is a consultant for Precision Health. OAA is consultant for Cortechs.ai and Precision Health, and has received speaker\u2019s honorarium from Lundbeck, Janssen, Otsuka and Sunovion.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}