8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer.

Title8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer.
Publication TypeJournal Article
Year of Publication2020
AuthorsDupont, WD, Breyer, JP, W Plummer, D, Chang, SS, Cookson, MS, Smith, JA, Blue, EE, Bamshad, MJ, Smith, JR
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalNat Commun
Date Published2020 03 23
KeywordsAged, Case-Control Studies, Chromosomes, Human, Pair 8, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Heterozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Mutation, Prostatic Neoplasms, Protective Factors, Risk Factors

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

Alternate JournalNat Commun
PubMed ID32251286
PubMed Central IDPMC7089954
Grant ListU24 HG008956 / HG / NHGRI NIH HHS / United States
P30 CA068485 / CA / NCI NIH HHS / United States
S10 OD021553 / OD / NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
UL1 TR000445 / TR / NCATS NIH HHS / United States