TY - JOUR
T1 - Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4
AU - Goddard, Katrina A B
AU - Witte, John S.
AU - Suarez, Brian K.
AU - Catalona, William J.
AU - Olson, Jane M.
N1 - Funding Information:
This work was supported, in part, by U.S. Public Health Service grants HG01577 from the National Center for Human Genome Research, RR03655 from the National Center for Research Resources, CA88164 from the National Cancer Institute, and MH14677; by U.S. Army Medical Research and Material Command grants DAMD17-00-10108 and DAMD17-98-1-8589; and by grants from the Urologic Research Foundation. Some of the results in this article were obtained by S.A.G.E. software, which is supported by National Center for Research Resources grant RR03655.
PY - 2001
Y1 - 2001
N2 - As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions. In the present study, we model locus heterogeneity among affected sib pairs with prostate cancer by including covariates in the linkage analysis that serve as surrogate measures of between-family linkage differences. The model is a modification of the Olson conditional logistic model for affected relative pairs. By including Gleason score, age at onset, male-to-male transmission, and/or number of affected first-degree family members as covariates, we detected linkage near three locations that were previously identified by linkage (1q24-25 [HPC1; LOD score 3.25, P = .00012], 1q42.2-43 [PCAP; LOD score 2.84, P = .0030], and 4q [LOD score 2.80, P = .00038]), near the androgen-receptor locus on Xq12-13 (AR; LOD score 3.06, P = .00053), and at five new locations (LOD score > 2.5). Without covariates, only a few weak-to-moderate linkage signals were found, none of which replicate findings of previous genome scans. We conclude that covariate-based linkage analysis greatly improves the likelihood that linked regions will be found by incorporation of information about heterogeneity within the sample.
AB - As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions. In the present study, we model locus heterogeneity among affected sib pairs with prostate cancer by including covariates in the linkage analysis that serve as surrogate measures of between-family linkage differences. The model is a modification of the Olson conditional logistic model for affected relative pairs. By including Gleason score, age at onset, male-to-male transmission, and/or number of affected first-degree family members as covariates, we detected linkage near three locations that were previously identified by linkage (1q24-25 [HPC1; LOD score 3.25, P = .00012], 1q42.2-43 [PCAP; LOD score 2.84, P = .0030], and 4q [LOD score 2.80, P = .00038]), near the androgen-receptor locus on Xq12-13 (AR; LOD score 3.06, P = .00053), and at five new locations (LOD score > 2.5). Without covariates, only a few weak-to-moderate linkage signals were found, none of which replicate findings of previous genome scans. We conclude that covariate-based linkage analysis greatly improves the likelihood that linked regions will be found by incorporation of information about heterogeneity within the sample.
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U2 - 10.1086/320103
DO - 10.1086/320103
M3 - Article
C2 - 11309685
AN - SCOPUS:0035025453
SN - 0002-9297
VL - 68
SP - 1197
EP - 1206
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -