{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T10:33:19Z","timestamp":1772620399725,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T00:00:00Z","timestamp":1710201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT2024867"],"award-info":[{"award-number":["GNT2024867"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL]). Inference is made from the changes in regression coefficients of relatives' PRSs or PRS and family history before and after adjusting for each other. We applied these approaches to two breast cancer PRSs and multiple studies and found that\u00a0(a) for breast cancer diagnosed at a young age, for example,\u00a0&lt;50 years, there was no evidence that the PRSs were causal, while (b) for breast cancer diagnosed at later ages, there was consistent evidence for causation explaining increasing amounts of the PRS\u2010disease association. The genetic variants in the PRS might be in linkage disequilibrium with truly causal variants and not causal themselves. These PRSs cause minimal heritability of breast cancer at younger ages. There is also evidence for nongenetic factors shared by first\u2010degree relatives that explain breast cancer familial aggregation. Familial associations are not necessarily due to genes, and genetic associations are not necessarily causal.<\/jats:p>","DOI":"10.1002\/gepi.22556","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T04:38:48Z","timestamp":1710304728000},"page":"401-413","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Causation and familial confounding as explanations for the associations of polygenic risk scores with breast cancer: Evidence from innovative ICE FALCON and ICE CRISTAL analyses"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-8594","authenticated-orcid":false,"given":"Shuai","family":"Li","sequence":"first","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria Australia"},{"name":"Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care University of Cambridge Cambridge UK"},{"name":"Precision Medicine, School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia"},{"name":"Murdoch Children's Research Institute Royal Children's Hospital Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian S.","family":"Dite","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria Australia"},{"name":"Genetic Technologies Ltd. Fitzroy Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"MacInnis","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria Australia"},{"name":"Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minh","family":"Bui","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuong L.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivienne F. C.","family":"Esser","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0884-4246","authenticated-orcid":false,"given":"Zhoufeng","family":"Ye","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James G.","family":"Dowty","sequence":"additional","affiliation":[{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne Carlton Victoria 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