Browsing by Author "Berndt, S.I."
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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.Item A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer(Nature Genetics, 2014-09) Al Olama, A.A.; Kote-Jarai, Z.; Berndt, S.I.; Conti, D.V.; Schumacher, F.; Biritwum, R.B.; Yao, T.Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.Item Two susceptibility loci identified for prostate cancer aggressiveness.(Nature Communications, 2015-05) Berndt, S.I.; Wang, Z.; Yeager, M.; Alavanja, M.C.; Albanes, D.; Amundadottir, L.; Andriole, G.; Beane Freeman, L.; Campa, D.; Cancel-Tassin, G.; Canzian, F.; Cornu, J.-N.; Cussenot, O.; Diver, W.R.; Gapstur, S.M.; Grönberg, H.; Haiman, C.A.; Henderson, B.; Hutchinson, A.; Hunter, D.J.; Key, T.J.; Kolb, S.; Koutros, S.; Kraft, P.; Le Marchand, L.; Lindström, S.; Machiela, M.J.; Ostrander, E.A.; Riboli, E.; Schumacher, F.; Siddiq, A.; Stanford, J.L.; Stevens, V.L.; Travis, R.C.; Tsilidis, K.K.; Virtamo, J.; Weinstein, S.; Wilkund, F.; Xu, J.; Lilly Zheng, S.; Yu, K.; Wheeler, W.; Zhang, H.; Sampson, J.; Black, A.; Jacobs, K.; Hoover, R.N.; Tucker, M.; Chanock, S.J.Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.