Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10^-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10^-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10^-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa¹.

Fig. 1 |. ELLIPSE/PRACTICAL study overview of PrCa GWAS meta-analysis.

The top section describes the PrCa GWAS meta-analysis published in 2014, in which 23 novel variants were identified. The current PrCa GWAS meta-analysis incorporated an additional 46,939 PrCa cases and 27,910 controls independent of the meta-analyses. The current meta-analysis discovered 62 novel variants associated with overall PrCa and 1 novel variant associated with early-onset PrCa.

Fig. 2 |. Locus Explorer plots depicting the statistical association with PrCa and biological context of variants from four of the newly identified PrCa-risk loci (n = 74,849 biologically independent samples).

a-d, Top, Manhattan plots of variant −log₁₀ P values (y axis), with the Index SNP labeled. Variants that were directly genotyped with the OncoArray are represented as triangles, and imputed variants are represented as circles. Variants in LD with the index SNP are denoted by color (red, r² >0.8; orange, 0.6 < r² < 0.8; yellow, 0.4 < r² < 0.6; green, 0.2 < r² < 0.4, blue, r² ≤0.2). Middle, relative locations of selected biological annotations: histone marks within seven cell lines from the ENCODE project; genes for which the index SNP is an eQTL in TCGA prostate adenocarcinoma dataset; chromatin state annotation by ChromHMM in PrEC cells; conserved elements within the genome; and DNAse I-hypersensitivity sites in ENCODE prostate cell lines. Bottom, positions of genes within the region, with genes on the positive and negative strands marked in green and purple, respectively. The horizontal axis represents genomic coordinates in the hg19 reference genome. a, rs1800057 (chromosome (chr) 11: 107643000–108644000). The index variant is a nonsynonymous SNP in ATM. b, rs1048160 (chr 9: 18556000–19557000). The index variant is located within the 3′ UTR of HAUS6 and is an eQTL for HAUS6. c, rs7968403 (chr 12: 64513000–65514000). The signal is centered on RASSF3, and the index variant is located within the first intron. This SNP is also situated within a region annotated for multiple regulatory markers and is an eQTL for the more distant WIF1 gene. d, rs28441558 (chr 17: 7303000–8304000). The signal implicates a cluster of highly correlated variants centered on CHD3. The index SNP is also an eQTL for three other more distantly located genes.