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However, none of these differences have been found to associate with schizophrenia polygenic risk. Here, in a large sample (<jats:italic>n<\/jats:italic>\u2009=\u200914,701) of unaffected participants from the UK Biobank, we test whether schizophrenia polygenic risk scores (PRS) limited to specific gene-sets predict subcortical brain volumes. We compare associations with schizophrenia PRS at the whole genome level (\u2018genomic\u2019, including all SNPs associated with the disorder at a<jats:italic>p<\/jats:italic>-value threshold &lt;\u20090.05) with \u2018genic\u2019 PRS (based on SNPs in the vicinity of known genes), \u2018intergenic\u2019 PRS (based on the remaining SNPs), and genic PRS limited to SNPs within 7 gene-sets previously found to be enriched for genetic association with schizophrenia (\u2018abnormal behaviour,\u2019 \u2018abnormal long-term potentiation,\u2019 \u2018abnormal nervous system electrophysiology,\u2019 \u2018FMRP targets,\u2019 \u20185HT2C channels,\u2019 \u2018CaV2 channels\u2019 and \u2018loss-of-function intolerant genes\u2019). We observe a negative association between the \u2018abnormal behaviour\u2019 gene-set PRS and volume of the right thalamus that survived correction for multiple testing (\u00df\u2009=\u2009\u22120.031, p<jats:sub>FDR<\/jats:sub>\u2009=\u20090.005) and was robust to different schizophrenia PRS<jats:italic>p<\/jats:italic>-value thresholds. In contrast, the only association with genomic PRS surviving correction for multiple testing was for right pallidum, which was observed using a schizophrenia PRS<jats:italic>p<\/jats:italic>-value threshold &lt;\u20090.01 (\u00df\u2009=\u2009\u22120.032,<jats:italic>p<\/jats:italic>\u2009=\u20090.0003, p<jats:sub>FDR<\/jats:sub>\u2009=\u20090.02), but not when using other PRS<jats:italic>P<\/jats:italic>-value thresholds. We conclude that schizophrenia PRS limited to functional gene sets may provide a better means of capturing differences in subcortical brain volume than whole genome PRS approaches.<\/jats:p>","DOI":"10.1038\/s41398-020-00940-0","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T12:53:14Z","timestamp":1599742394000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort"],"prefix":"10.1038","volume":"10","author":[{"given":"Steluta","family":"Grama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Willcocks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Hubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6845-7590","authenticated-orcid":false,"given":"Antonio F.","family":"Pardi\u00f1as","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-0289","authenticated-orcid":false,"given":"Sophie E.","family":"Legge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0531-6309","authenticated-orcid":false,"given":"Matthew","family":"Bracher-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6600-6507","authenticated-orcid":false,"given":"Georgina E.","family":"Menzies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-5303","authenticated-orcid":false,"given":"Lynsey S.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2137-0452","authenticated-orcid":false,"given":"Andrew J.","family":"Pocklington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J. 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