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Christensen GB , Baffoe-Bonnie AB , George A , Powell I , Bailey-Wilson JE , Carpten JD , Giles GG , Hopper JL , Seven G , English DR , Foulkes WD , Maehle L , Moller P , Eeles R , Easton D , Badzioch MD , Whittemore AS , Oakley-Girvan I , Hsieh CL , Dimitrov L , Xu JF , Stanford JL , Johanneson B , Deutsch K , McIntosh L , Ostrander EA , Wiley KE , Isaacs SD , Walsh PC , Isaacs WB , Thibodeau SN , McDonnell SK , Hebbring S , Schaid DJ , Lange EM , Cooney KA , Tammela TLJ , Schleutker J , Paiss T , Maier C , Gronberg H , Wiklund F , Emanuelsson M , Farnham JM , Cannon-Albright LA , Camp NJ , Int Consortium Prostate Canc Genet; Int Consortium Prostate Canc Genet
Genome-Wide Linkage Analysis of 1,233 Prostate Cancer Pedigrees From the International Consortium for Prostate Cancer Genetics Using Novel sum LINK and sum LOD Analyses
Prostate. 2010 May;70(7) :735-744
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Abstract
BACKGROUND. Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS. We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS. Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS. Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate 70: 735-744, 2010. (C) 2010 Wiley-Liss, Inc.
Notes
Christensen, G. Bryce Baffoe-Bonnie, Agnes B. George, Asha Powell, Isaac Bailey-Wilson, Joan E. Carpten, John D. Giles, Graham G. Hopper, John L. Seven, Gianluca English, Dallas R. Foulkes, William D. Maehle, Lovise Moller, Pal Eeles, Ros Easton, Douglas Badzioch, Michael D. Whittemore, Alice S. Oakley-Girvan, Ingrid Hsieh, Chih-Lin Dimitrov, Latchezar Xu, Jianfeng Stanford, Janet L. Johanneson, Bo Deutsch, Kerry McIntosh, Laura Ostrander, Elaine A. Wiley, Kathleen E. Isaacs, Sarah D. Walsh, Patrick C. Isaacs, William B. Thibodeau, Stephen N. McDonnell, Shannon K. Hebbring, Scott Schaid, Daniel J. Lange, Ethan M. Cooney, Kathleen A. Tammela, Teuvo L. J. Schleutker, Johanna Paiss, Thomas Maier, Christiane Gronberg, Henrik Wiklund, Fredrik Emanuelsson, Monica Farnham, James M. Cannon-Albright, Lisa A. Camp, Nicola J. Wiley-liss Hoboken 591xm