Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.

Hum Genet 2016 08 4;135(8):923-38. Epub 2016 Jun 4.

Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA.

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-016-1690-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020907PMC
August 2016
57 Reads
4 Citations
4.824 Impact Factor

Publication Analysis

Top Keywords

prostate cancer
20
cancer cases
8
genome-wide association
8
familial prostate
8
risk-allele carriers
8
prostate
5
cancer
5
achieved large
4
estimated size
4
large estimated
4
8q2421 achieved
4
snp rs138042437
4
note snp
4
size cohort
4
rs138042437 p = 17e-8
4
p = 17e-8 8q2421
4
116 sampled
4
relatives risk-allele
4
carriers
4
carriers gwas
4

References

(Supplied by CrossRef)

GR Abecasis et al.
Nature 2012

I Agalliu et al.
Clin Cancer Res 2009

A Al Olama et al.
Hum Mol Genet 2015

AA Al Olama et al.
Nat Genet 2009

AA Al Olama et al.
Hum Mol Genet 2013

AA Al Olama et al.
Nat Genet 2014

LT Amundadottir et al.
Nat Genet 2006

SI Berndt et al.
Nat Commun 2015

A Bureau et al.
Bioinformatics 2014

H Chen et al.
Prostate 2015

GB Christensen et al.
Prostate 2007

Similar Publications