期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 19, 页码 5603-5618出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv269
关键词
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资金
- National Institutes of Health (NIH), National Cancer Institute (NCI) GAME-ON U19 initiative for prostate cancer (ELLIPSE) [CA148537]
- NIH/NCI [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]
- NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics
- NIH
- NCI
- U.S. Public Health Service from the NCI, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]
- Cancer Risk Prediction Center (CRisP)
- Linneus Centre - Swedish Research Council [70867902, K2010-70X-20430-04-3]
- Swedish Cancer Foundation [09-0677]
- Hedlund Foundation
- Soderberg Foundation
- Enqvist Foundation
- Stockholm County Council
- Stiftelsen Johanna Hagstrand och Sigfrid Linner's Minne
- Karlsson's Fund for urological and surgical research
- NIH [CA63464, CA54281, CA1326792, CA148085, HG004726, CA056678, CA082664, CA092579, ES011126, S06GM08016, CA092447, CA098758]
- Division of Cancer Epidemiology and Genetics, NCI, NIH
- Cancer Research Fund [99-00524V-10258]
- Department of Health Services Cancer Research Program [97-12013, 98-00924V]
- NCI, NIH, Department of Health and Human Services [N01-PC-35139]
- California Department of Health Services [103885]
- Centers for Disease Control and Prevention [1U58DP000807-3]
- Fred Hutchinson Cancer Research Center
- National Human Genome Research Institute
- DOD [W81XWH-07-1-0122, DAMD W81XWH-07-1-0203, DAMD W81XWH-06-1-0066, W81XWH-10-1-0532]
- American Cancer Society
- Public Health Service from the National Cancer Institute [CA37429, 5UM1CA182883]
- National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC)
- NIH/National Human Genome Research Institute [U01 HG004726-01]
- Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government
- Princess Takamatsu Cancer Research Fund
- Takeda Science Foundation
- [CA136924]
- [CA68578]
- [ES007784]
- [DAMD W81XWH-07-1-0645]
- [CA140388]
- [U01 HG004446]
- [R01 CA136924]
- [R01 GM107427]
- Cancer Research UK [16491, 16563, 17528, 19170, 15007] Funding Source: researchfish
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 genome-encoded 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 x 10(-4)-5.6 x 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 x 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.
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