TY - JOUR
T1 - Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21
AU - Teerlink, Craig
AU - Leongamornlert, Daniel
AU - Dadaev, Tokhir
AU - Thomas, Alun
AU - Farnham, James
AU - Stephenson, Robert A.
AU - Riska, Shaun
AU - McDonnell, Shannon K.
AU - Schaid, Daniel J.
AU - Catalona, William J.
AU - Zheng, S. Lilly
AU - Cooney, Kathleen A.
AU - Ray, Anna M.
AU - Zuhlke, Kimberly A.
AU - Lange, Ethan M.
AU - Giles, Graham G.
AU - Southey, Melissa C.
AU - Fitzgerald, Liesel M.
AU - Rinckleb, Antje E.
AU - Luedeke, Manuel
AU - Maier, Christiane
AU - Stanford, Janet L.
AU - Ostrander, Elaine A.
AU - Kaikkonen, Elina M.
AU - Sipeky, Csilla
AU - Tammela, Teuvo L.J.
AU - Schleutker, Johanna
AU - Wiley, Kathleen E.
AU - Isaacs, Sarah D.
AU - Walsh, Patrick C.
AU - Isaacs, William B.
AU - Xu, Jianfeng
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Olivier
AU - Mandal, Diptasri
AU - Laurie, Cecelia
AU - Laurie, Cathy
AU - Thibodeau, Stephen N.
AU - Eeles, Rosalind A
AU - Kote-Jarai, Zsofia
AU - Cannon-Albright, Lisa
AU - The PRACTICAL consortium
AU - International Consortium for Prostate Cancer Genetics
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978804629&partnerID=8YFLogxK
U2 - 10.1007/s00439-016-1690-6
DO - 10.1007/s00439-016-1690-6
M3 - Article
C2 - 27262462
AN - SCOPUS:84978804629
SN - 0340-6717
VL - 135
SP - 923
EP - 938
JO - Human Genetics
JF - Human Genetics
IS - 8
ER -
