Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men

Abstract

A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.

Fig. 1.

Summary of results for the whole-genome admixture scan and characteristics of the 8q24 peak of association. (a) We present the LOD score at equally spaced points across the genome. The chromosome 8 peak is marked by a rise to 7.14. (b) We can use the data to calculate a probability distribution for the position of the peak. It aligns with the microsatellite and SNP recently associated with prostate cancer by Amundadottir et al. (13) (dashed line). (c) The 95% credible interval spans 3.8 Mb (125.68–129.48 Mb in build 35 of the human reference sequence) and contains nine known genes, including the c-MYC oncogene (diagram taken from http://genome.ucsc.edu) (data from the May 2004 genome assembly).

Fig. 2.

To formally test for a relationship between age of onset and contribution to the chromosome 8 locus, we rank-ordered the individuals by age of onset and then calculated a score for increasing age cutoffs. The score rises to 5.40 above the expectation for 1,176 individuals diagnosed at <72 years of age. To evaluate whether this rise is unexpected, we permuted the data 1,000,000 times, randomizing scores with respect to individuals' ages of onset (guaranteeing that there is no relationship between age of diagnosis and contribution to the evidence of association). In only 318 of 1,000,000 permutations did we see a rise as high as in our data (P < 0.00032).