Risk of breast and prostate cancer is not associated with increased homozygosity in outbred populations

Abstract

Regions of restricted genetic heterogeneity due to identity by descent (autozygosity) are known to confer susceptibility to a number of diseases. Regions of germline homozygosity (ROHs) of 1-2 Mb, the result of autozygosity, are detectable at high frequency in outbred populations. Recent studies have reported that ROHs, possibly through exposing recessive disease-causing alleles or alternative mechanisms, are associated with an increased cancer risk. To examine whether homozygosity is associated with breast or prostate cancer risk, we analysed 500K single-nucleotide polymorphism data from two genome-wide association studies conducted by the Cancer Genetics Markers of Susceptibility initiatives (http://cgems.cancer.gov/). Six common ROHs were associated with breast cancer risk and four with prostate cancer (P<0.01). Intriguingly, one of the breast cancer ROHs maps to 6q22.31-6q22.3, a region that has been previously shown to confer breast cancer risk. Although none of the ROHs remained significantly associated with cancer risk after adjustment for multiple testing, a number of ROHs merit further interrogation. However, our findings provide no strong evidence that levels of measured homozygosity, whatever their aetiology (autozygosity, uniparental isodisomy or hemizygosity), confer an increased risk of developing breast or prostate cancer in predominantly outbred populations.

Figure 1

Comparison of ethnicity in each of the sample series. The first two principal components of the analysis were plotted. HapMap data are plotted in grey; CEU individuals as ‘•' CHB+JPT individuals as ‘▴' and YRI individuals as ‘+'. Plotted in black, as ‘X', are (a) breast cancer cases, (b) prostate cancer cases, (c) breast cancer controls and (d) prostate cancer controls.

Figure 2

Genome-wide plots showing the location of each run of homozygosity among the genomes in (a) breast cancer cases and (b) controls; (c) prostate cancer cases and (d) controls. The threshold limit was set to a minimum of at least 80 consecutive homozygous SNPs.

Figure 3

Cumulative distributions of ROH in breast cancer and prostate cancer series. The graph is presented in such a way that each data point represents the cumulative fraction (y axis) of samples with the corresponding minimum cumulative run of homozygosity (x axis).