Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset.
Previous studies have suggested strong evidence for a hereditary component to prostate cancer (PC) susceptibility. Here, we analyze 3,796 individuals in 263 PC families recruited as part of the ongoing Prostate Cancer Genetic Research Study (PROGRESS). We use Markov chain Monte Carlo (MCMC) oligogenic segregation analysis to estimate the number of quantitative trait loci (QTLs) and their contribution to the variance in age at onset of hereditary PC (HPC). We estimate 2 covariate effects: diagnosis of PC before and after prostate-specific antigen (PSA) test availability, and presence/absence of at least 1 blood relative with primary neuroepithelial brain cancer (BC). We find evidence that 2 to 3 QTLs contribute to the variance in age at onset of HPC. The 2 QTLs with the largest contribution to the total variance are both effectively dominant loci. We find that the covariate for diagnosis before and after PSA test availability is important. Our findings for the number of QTLs contributing to HPC and the variance contribution of these QTLs will be instructive in mapping and identifying these genes.
Division of Medical Genetics, Department of Medicine, University of Washington, Box 357720, Seattle, WA 98195-7720, USA.
Erin M
EM
Conlon
Ellen L
EL
Goode
Mark
M
Gibbs
Janet L
JL
Stanford
Michael
M
Badzioch
Marta
M
Janer
Suzanne
S
Kolb
Lee
L
Hood
Elain A
EA
Ostrander
Gail P
GP
Jarvik
Ellen M
EM
Wijsman
D000230:Adenocarcinoma / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood; D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000097:blood; D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics; D020090:Chromosome Segregation; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology / Q000235:genetics*; D018242:Neuroectodermal Tumors, Primitive / Q000453:epidemiology / Q000235:genetics; D010375:Pedigree; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D040641:Quantitative Trait Loci; D014481:United States / Q000453:epidemiology
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen