title: Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions.
abstract: 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 × 10(-4)-5.6 × 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 × 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.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine.
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authors.affiliation: Department of Preventive Medicine, Keck School of Medicine.
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authors.lastname: Hazelett
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
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authors.lastname: Wiklund
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center.
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authors.lastname: Schumacher
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center.
authors.forename: Daniel O
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sonja I
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authors.lastname: Berndt
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, Cancer Genomics Research Laboratory, NCI-DCEG, SAIC-Frederick Inc., Frederick, MD, USA.
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authors.lastname: Wang
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine.
authors.forename: Kristin A
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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authors.affiliation: Cancer Genomics Research Laboratory, NCI-DCEG, SAIC-Frederick Inc., Frederick, MD, USA.
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authors.lastname: Yeager
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, Cancer Genomics Research Laboratory, NCI-DCEG, SAIC-Frederick Inc., Frederick, MD, USA.
authors.forename: Laurie
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, Cancer Genomics Research Laboratory, NCI-DCEG, SAIC-Frederick Inc., Frederick, MD, USA.
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authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center.
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authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center.
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mesh_terms: D044466:Asian People / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics*; D040641:Quantitative Trait Loci; D044465:White People / Q000235:genetics*