{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:38:17Z","timestamp":1792100297785,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T00:00:00Z","timestamp":1595289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["R01 MH121924"],"award-info":[{"award-number":["R01 MH121924"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Polygenic risk scores (PRSs) have become an increasingly popular approach for demonstrating polygenic influences on complex traits and for establishing common polygenic signals between different traits. PRSs are typically constructed using pruning and thresholding (P+T), but the best choice of parameters is uncertain; thus multiple settings are used and the best is chosen. Optimization can lead to inflated Type I error. Permutation procedures can correct this, but they can be computationally intensive. Alternatively, a single parameter setting can be chosen a priori for the PRS, but choosing suboptimal settings results in loss of power. We propose computing PRSs under a range of parameter settings, performing principal component analysis (PCA) on the resulting set of PRSs, and using the first PRS\u2013PC in association tests. The first PC reweights the variants included in the PRS to achieve maximum variation over all PRS settings used. Using simulations and a real data application to study PRS association with bipolar disorder and psychosis in bipolar disorder, we compare the performance of the proposed PRS\u2013PCA approach with a permutation test and an a priori selected\n                    <jats:italic>p<\/jats:italic>\n                    \u2010value threshold. The PRS\u2013PCA approach is simple to implement, outperforms the other strategies in most scenarios, and provides an unbiased estimate of prediction performance.\n                  <\/jats:p>","DOI":"10.1002\/gepi.22339","type":"journal-article","created":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T03:40:40Z","timestamp":1595302840000},"page":"676-686","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["A principal component approach to improve association testing with polygenic risk scores"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4322-5923","authenticated-orcid":false,"given":"Brandon J.","family":"Coombes","sequence":"first","affiliation":[{"name":"Department of Health Sciences Research Mayo Clinic  Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5042-8326","authenticated-orcid":false,"given":"Alexander","family":"Ploner","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5888-0034","authenticated-orcid":false,"given":"Sarah E.","family":"Bergen","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9350-4440","authenticated-orcid":false,"given":"Joanna M.","family":"Biernacka","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research Mayo Clinic  Rochester Minnesota"},{"name":"Department of Psychiatry and Psychology Mayo Clinic  Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2019.0257"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20448"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2018.17040467"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2016.09.381"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giz082"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22150"},{"key":"e_1_2_8_8_1","article-title":"Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores","author":"Coombes B.","year":"2020","journal-title":"MedRxiv"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910666116"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0269-7"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2019.4079"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.77"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40345-015-0030-4"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2019.11.109"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.154"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08185"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0361-7"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0147-3"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.11.020"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2019.10.011"},{"key":"e_1_2_8_22_1","first-page":"252270","article-title":"Polygenic scores for UK Biobank scale data","author":"Mak T. 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