A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

Abstract

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

Figure 1

Schematic view of a region on chromosome 8q24 containing several prostate cancer risk variants. a) Shown are imputed association results, using only results based on chip-genotyped subjects, for variants with P < 1E-4 in the Icelandic prostate cancer GWAS and located between 127.8 Mb and 128.8 Mb (Build 36) on 8q24. Green triangles denote imputed association results (-log(P-value) of the unconditional analysis. Purple crosses denote association results after step-1 of the conditional analysis (the logistic regression), red boxed denote association results after step-2, and orange circles denote association result after step-3. The red diamonds below the X-axis denote the previously reported prostate cancer risk SNPs on 8q24 in populations of European descent (1, rs12543663; 2, rs10086908^,; 3, rs1016343; 4, rs13252298; 5, rs16901979; 6, rs16902094; 7, rs445114 / rs620861^,; 8, rs6983267; 9, rs1447295) and the two blue diamonds denote the two SNPs (A, rs183373024 and B, rs188140481) discussed in the main text. b) Shown are the CEU HapMap population recombination rate and the pairwise correlation coefficient (r²) for SNPs in the 1 megabase (Mb) region depicted. The annotations of blocks/regions is as previously described ^–,,.