Abstract B14: Population genetics analysis of prostate cancer GWAS SNPs to evaluate West African genetic ancestry as a risk factor

Abstract

Abstract Background: Prostate cancer (Pca) is the most common cancer among men in the U.S., and African American (AA) men have higher incidence compared to European American men. Environmental and sociocultural factors may play a role for increasing Pca risk among AA men, but the causal relationship of any environmental and social/cultural factors with Pca risk is not well demonstrated. On the other hand, there is strong evidence for genetic factors that explain increased incidence in AAs. Admixture mapping identified loci at 8q24 region showing association between African genetic ancestry and Pca risk, and a genome-wide association study (GWAS) in AAs identified a novel locus at 17q21 associated with Pca. However, replication of variants identified in GWAS among European and Asian populations has been difficult in AAs. Here, we performed population genetics analyses of Pca GWAS identified single nucleotide polymorphisms (SNPs) to evaluate whether these SNPs are informative of genetic ancestry and whether West African genetic Ancestry (WAA) is a Pca risk factor. Samples and Methods: We accessed National Human Genome Research Institute GWAS catalog in December, 2012, and there were 80 SNPs reported in 17 studies. We downloaded genotype data of 76 SNPs in 1000 Genomes (1KG) Project Phase I May 2011 and 62 SNPs in Human Genome Diversity Project (HGDP) from SPSmart. We performed principal component analysis using Golden Helix SVS 7. STRUCTURE was also used to estimate genetic ancestry and examine population clustering patterns. Replication study subjects, 470 AA men from Washington, DC (220 Pca cases and 250 controls) were genotyped as a part of GWAS in AAs with Illumina Infinium 1M. Logistic regression analysis was performed adjusting for age and 5 principal components (PCs). Results: Mean heterozygosity of 76 Pca GWAS SNPs in the 1KG Project dataset was lower in African populations than in European populations, possibly due to ascertainment bias. The majority of Pca GWAS SNPs had FST less than 0.20, but rs9623117 on chromosome 22 was highly differentiated (FST=0.63). In the 1KG Project dataset, PC1 separated African populations from non-African populations, and PC2 reflects variation in non-African populations separating East Asian from European populations. AA (ASW) individuals fell between the African and European clusters. Fewer Pca GWAS SNPs were genotyped in HGDP dataset, but they successfully captured global human genome variation forming African and non-African population clusters. In the STRUCTURE analysis with the 1KG project dataset, K=2 separated African from non-African populations, and K=3 separated European from East Asian populations. WAA estimated using 76 Pca GWAS SNPs was significantly correlated with WAA estimated using ancestry informative markers. Only four Pca GWAS SNPs were replicated and three of them were independently associated (P<0.05) in our replication samples. The number of risk alleles were positively associated with Pca risk (PTREND=0.002), and AAs carrying ≥5 risk alleles had 3.5 times greater odds of Pca (95% C.I.; 1.36-9.17; P=0.009) compared to AAs with ≤ 2 risk alleles. Risk allele frequencies of the three independently associated SNPs were higher in West Africans than in Europeans and was positively correlated with WAA estimates (PANOVA<0.001). Conclusion: Results of our analyses provide evidence suggesting that WAA is a risk factor for Pca. Population genetics analyses show that Pca GWAS SNPs can successfully capture global human genome variation and are informative of genetic ancestry. AAs with high WAA are likely to carry more Pca risk alleles than AAs with low WAA. Citation Format: Ken Batai, Ebony Shah, Rick A. Kittles. Population genetics analysis of prostate cancer GWAS SNPs to evaluate West African genetic ancestry as a risk factor. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B14. doi:10.1158/1538-7755.DISP13-B14