Integration of Multiethnic Fine-Mapping and Genomic Annotation to Prioritize Candidate Functional SNPs at Prostate Cancer Susceptibility Regions

Hum Mol Genet. 2015 Oct 1;24(19):5603-18. doi: 10.1093/hmg/ddv269. Epub 2015 Jul 10.

Abstract

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • African Continental Ancestry Group / genetics*
  • Asian Continental Ancestry Group / genetics*
  • Chromosome Mapping / methods
  • European Continental Ancestry Group / genetics*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Hispanic Americans / genetics*
  • Humans
  • Linkage Disequilibrium
  • Male
  • Molecular Sequence Annotation
  • Polymorphism, Single Nucleotide*
  • Prostatic Neoplasms / ethnology
  • Prostatic Neoplasms / genetics*
  • Quantitative Trait Loci

Grant support