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Am J Hum Genet. 2018 Jun 7;102(6):1048-1061. doi: 10.1016/j.ajhg.2018.04.001. Epub 2018 May 17.

Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative.

Author information

1
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, 7491 Trondheim, Sør-Trøndelag, Norway.
2
USC Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
3
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Michigan Institute for Data Science, University of Michigan, Ann Arbor, MI 48109, USA.
4
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
5
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
6
Division of Pain Medicine, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
7
Central Biorepository, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
8
Division of Pain Medicine, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI 48109, USA.
9
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Michigan Institute for Data Science, University of Michigan, Ann Arbor, MI 48109, USA; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: bhramar@umich.edu.

Abstract

Health systems are stewards of patient electronic health record (EHR) data with extraordinarily rich depth and breadth, reflecting thousands of diagnoses and exposures. Measures of genomic variation integrated with EHRs offer a potential strategy to accurately stratify patients for risk profiling and discover new relationships between diagnoses and genomes. The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine. PRS for 12 cancer traits were calculated using summary statistics from the NHGRI-EBI catalog. A total of 1,711 synthetic case-control studies was used for PheWAS analyses. There were 13,490 (47.7%) patients with at least one cancer diagnosis in this study sample. PRS exhibited strong association for several cancer traits they were designed for, including female breast cancer, prostate cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, and thyroid cancer. Phenome-wide significant associations were observed between PRS and many non-cancer diagnoses. To differentiate PRS associations driven by the primary trait from associations arising through shared genetic risk profiles, the idea of "exclusion PRS PheWAS" was introduced. Further analysis of temporal order of the diagnoses improved our understanding of these secondary associations. This comprehensive PheWAS used PRS instead of a single variant.

KEYWORDS:

electronic health records; genetic variation; genome-wide association study; hospitals; humans; multifactorial inheritance; neoplasms; phenome-wide association study; phenotype; risk

PMID:
29779563
PMCID:
PMC5992124
DOI:
10.1016/j.ajhg.2018.04.001
[Indexed for MEDLINE]
Free PMC Article

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