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

S Li; GS Dite; RJ MacInnis; M Bui; TL Nguyen; VFC Esser; Z Ye; JG Dowty; E Makalic; J Sung; GG Giles; MC Southey; JL Hopper

Journal article

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

S Li, GS Dite, RJ MacInnis, M Bui, TL Nguyen, VFC Esser, Z Ye, JG Dowty, E Makalic, J Sung, GG Giles, MC Southey, JL Hopper

Genetic Epidemiology | WILEY | Published : 2024

DOI: 10.1002/gepi.22556

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Abstract

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 eac..

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University of Melbourne Researchers

Shuai Li Author

Gillian Dite Author

Robert MacInnis Author

Minh Bui Author

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Grants

Awarded by Cancer Council Victoria

Funding Acknowledgements

The UK Biobank resource used in this study was accessed under Application Number 47401. This study is supported by National Health and Medical Research Council (NHMRC) grant GNT2024867. The ABCFR was supported in Australia by NHMRC, the New South Wales Cancer Council, the Victorian Health Promotion Foundation, the Victorian Breast Cancer Research Consortium, Cancer Australia, and the National Breast Cancer Foundation. The six sites of the Breast Cancer Family Registry (BCFR) were supported by grant UM1 CA164920 from the U.S. National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the BCFR, nor does mention of trade names, commercial products, or organisations imply endorsement by the U.S. Government or the BCFR. MCCS cohort recruitment was funded by Cancer Council Victoria and VicHealth. The MCCS was further supported by NHMRC grants 209057, 396414, 1074383, and 1129136, and ongoing follow-up and data management have been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. S. L. is an NHMRC Emgerging Leadership Fellow (GNT2017373). M. C. S. is an NHMRC Leadership Fellow. J. L. H. is a Dame Kate Campbell Professorial Fellow of the University of Melbourne. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.