Browsing by Author "Chung, C.C."
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Item A comprehensive resequence-analysis of 250 kb region of 8q24.21 in men of African ancestry(Prostate, 2014-05) Chung, C.C.; Hsing, A.W.; Yeboah, E.; Biritwum, R.; Tettey, Y.; Adjei, A.; Cook, M.B.; De Marzo, A.; Netto, G.; Tay, E.; Boland, J.F.; Yeager, M.; Chanock, S.J.BACKGROUND Genome-wide association studies (GWAS) have identified that a ∼1 M region centromeric to the MYC oncogene on chromosome 8q24.21 harbors at least five independent loci associated with prostate cancer risk and additional loci associated with cancers of breast, colon, bladder, and chronic lymphocytic leukemia (CLL). Because GWAS identify genetic markers that may be indirectly associated with disease, fine-mapping based on sequence analysis provides important insights into patterns of linkage disequilibrium (LD) and is critical in defining the optimal variants to nominate for biological follow-up. METHODS To catalog variation in individuals of African ancestry, we resequenced a region (250 kb; chr8:128,050,768-128,300,801, hg19) containing several prostate cancer susceptibility loci as well as a locus associated with CLL. Our samples included 78 individuals from Ghana and 47 of African-Americans from Johns Hopkins University. RESULTS After quality control metrics were applied to next-generation sequence data, 1,838 SNPs were identified. Of these, 285 were novel and not yet reported in any public database. Using genotypes derived from sequencing, we refined the LD and recombination hotspots within the region and determined a set of tag SNPs to be used in future fine-mapping studies. Based on LD, we annotated putative risk loci and their surrogates using ENCODE data, which should help guide laboratory studies. CONCLUSIONS In comparison to the 1000 Genome Project data, we have identified additional variants that could be important in establishing priorities for future functional work designed to explain the biological basis of associations between SNPs and both prostate cancer and CLL.© 2014 Wiley Periodicals, Inc.Item A genome-wide association study of prostate cancer in West African men(Human Genetics, 2014-05) Cook, M.B.; Wang, Z.; Yeboah, E.D.; Tettey, Y.; Biritwum, R.B.; Adjei, A.A.; Tay, E.; Truelove, A.; Niwa, S.; Chung, C.C.; Chokkalingam, A.P.; Chu, L.W.; Yeager, M.; Hutchinson, A.; Yu, K.; Rand, K.A.; Haiman, C.A.; Hoover, R.N.; Hsing, A.W.; Chanock, S.J.Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E-7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E-8), and SNPs at Xq28 (rs985081, p = 8.66E-9) and 6q21 (rs2185710, p = 5.95E-8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci. © 2013 Springer-Verlag Berlin Heidelberg (outside the USA).Item Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions(Human Molecular Genetics, 2015-07) Han, Y.; Hazelett, D.J.; Wiklund, F.; Schumacher, F.R.; Stram, D.O.; Berndt, S.I.; Wang, Z.; Rand, K.A.; Hoover, R.N.; Machiela, M.J.; Yeager, M.; Burdette, L.; Chung, C.C.; Hutchinson, A.; Yu, K.; Xu, J.; Travis, R.C.; Key, T.J.; Siddiq, A.; Canzian, F.; Takahashi, A.; Kubo, M.; Stanford, J.L.; Kolb, S.; Gapstur, S.M.; Ryan Diver, W.; Stevens, V.L.; Strom, S.S.; Pettaway, C.A.; Al Olama, A.A.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 genomeencoded 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 thatwere 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. © The Author 2015. Published by Oxford University Press. All rights reserved.