Browsing by Author "Machiela, M.J."
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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 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.