Abstract 4607: Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions
Authors: Han Ying , Hazelett Dennis J. , Henderson Brian E. , Conti David V. , Coetzee Gerhard A. , Haiman Christopher A. 
Published: August 2015

Background: 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 (LD). Due to the varying LD patterns and allele frequencies observed across racial/ethnic groups, studies in multiple populations have been suggested to increase power for fine-mapping by reducing the number of surrogates that are correlated with the underlying functional allele.

Methods: We examined 69 risk regions using genotyping and imputation-based fine-mapping in a large multiethnic sample comprised of 17,524 prostate cancer cases and 17,519 controls from populations of European (8,600 cases and 6,946 controls), African (5,327 cases and 5,136 controls), Asian (2,563 cases and 4,391 controls) and Latino (1,034 cases and 1,046 controls) ancestry. We then combined multiethnic fine-mapping results with detailed tissue-specific functional annotation (based upon epigenetic data and genome-encoded features) and expression quantitative trait loci (eQTL) analysis to localize and prioritize risk alleles for future laboratory testing.

Results: Markers at 57 regions passed a region-specific significance threshold (p-value cutoff range: 5.6×10−3-3.9×10−4) and in 32 regions we identified markers that better capture the association signals in the multiethnic sample. Novel secondary signals (p&lt;5.0×10−6) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 668 variants in the 57 regions with p-values within one order of magnitude of the most-associated marker, 200 variants (30%) in 48 regions overlapped with epigenetic or other putative functional marks. In 12 of the 57 regions, cis-eQTLs were detected with nearby genes. For 12 of the 57 regions (21%), the most-associated marker represented the strongest candidate functional variant based on annotations; the number of regions increased to 20 (35%) and 27 (47%) when examining the 2 and 3 most significantly associated variants in each region, respectively.

Conclusions: We have characterized 57 prostate cancer risk regions through statistical multiethnic fine-mapping, functional annotation and cis-eQTL analyses. The results have prioritized candidate variants for downstream functional evaluation to understand biological mechanisms at prostate cancer risk regions.

Citation Format: Ying Han, Dennis J. Hazelett, Brian E. Henderson, David V. Conti, Gerhard A. Coetzee, Christopher A. Haiman, on behalf of the GAME-ON/ELLIPSE Consortium. Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4607. doi:10.1158/1538-7445.AM2015-4607