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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.

SUBMITTER: Enciso-Mora V

PROVIDER: S-EPMC2987391 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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

Enciso-Mora Victor V Hosking Fay J FJ Houlston Richard S RS

European journal of human genetics : EJHG 20100421 8

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 ...[more]

PMID: 20407466

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Project description:Prior work in late-onset Alzheimer's disease (LOAD) has resulted in discrepant findings as to whether recent consanguinity and outbred autozygosity are associated with LOAD risk. In the current study, we tested the association between consanguinity and outbred autozygosity with LOAD in the largest such analysis to date, in which 20 LOAD GWAS datasets were retrieved through public databases. Our analyses were restricted to eight distinct ethnic groups: African-Caribbean, Ashkenazi-Jewish European, European-Caribbean, French-Canadian, Finnish European, North-Western European, South-Eastern European, and Yoruba African for a total of 21,492 unrelated subjects (11,196 LOAD and 10,296 controls). Recent consanguinity determination was performed using FSuite v1.0.3, according to subjects' ancestral background. The level of autozygosity in the outbred population was assessed by calculating inbreeding estimates based on the proportion (FROH) and the number (NROH) of runs of homozygosity (ROHs). We analyzed all eight ethnic groups using a fixed-effect meta-analysis, which showed a significant association of recent consanguinity with LOAD (N = 21,481; OR = 1.262, P = 3.6 × 10-4), independently of APOE ∗4 (N = 21,468, OR = 1.237, P = 0.002), and years of education (N = 9,257; OR = 1.274, P = 0.020). Autozygosity in the outbred population was also associated with an increased risk of LOAD, both for F ROH (N = 20,237; OR = 1.204, P = 0.030) and N ROH metrics (N = 20,237; OR = 1.019, P = 0.006), independently of APOE ∗4 [(F ROH, N = 20,225; OR = 1.222, P = 0.029) (N ROH, N = 20,225; OR = 1.019, P = 0.007)]. By leveraging the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data, we determined that LOAD subjects do not show an enrichment of rare, risk-enhancing minor homozygote variants compared to the control population. A two-stage recessive GWAS using ADSP data from 201 consanguineous subjects in the discovery phase followed by validation in 10,469 subjects led to the identification of RPH3AL p.A303V (rs117190076) as a rare minor homozygote variant increasing the risk of LOAD [discovery: Genotype Relative Risk (GRR) = 46, P = 2.16 × 10-6; validation: GRR = 1.9, P = 8.0 × 10-4]. These results confirm that recent consanguinity and autozygosity in the outbred population increase risk for LOAD. Subsequent work, with increased samples sizes of consanguineous subjects, should accelerate the discovery of non-additive genetic effects in LOAD.

Dataset Information

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

Publications

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

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