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Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

ABSTRACT: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P?=?2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

SUBMITTER: Saunders EJ

PROVIDER: S-EPMC3923678 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

Saunders Edward J EJ Dadaev Tokhir T Leongamornlert Daniel A DA Jugurnauth-Little Sarah S Tymrakiewicz Malgorzata M Wiklund Fredrik F Al Olama Ali Amin AA Benlloch Sara S Neal David E DE Hamdy Freddie C FC Donovan Jenny L JL Giles Graham G GG Severi Gianluca G Gronberg Henrik H Aly Markus M Haiman Christopher A CA Schumacher Fredrick F Henderson Brian E BE Lindstrom Sara S Kraft Peter P Hunter David J DJ Gapstur Susan S Chanock Stephen S Berndt Sonja I SI Albanes Demetrius D Andriole Gerald G Schleutker Johanna J Weischer Maren M Nordestgaard Børge G BG Canzian Federico F Campa Daniele D Riboli Elio E Key Tim J TJ Travis Ruth C RC Ingles Sue A SA John Esther M EM Hayes Richard B RB Pharoah Paul P Khaw Kay-Tee KT Stanford Janet L JL Ostrander Elaine A EA Signorello Lisa B LB Thibodeau Stephen N SN Schaid Daniel D Maier Christiane C Kibel Adam S AS Cybulski Cezary C Cannon-Albright Lisa L Brenner Hermann H Park Jong Y JY Kaneva Radka R Batra Jyotsna J Clements Judith A JA Teixeira Manuel R MR Xu Jianfeng J Mikropoulos Christos C Goh Chee C Govindasami Koveela K Guy Michelle M Wilkinson Rosemary A RA Sawyer Emma J EJ Morgan Angela A Easton Douglas F DF Muir Ken K Eeles Rosalind A RA Kote-Jarai Zsofia Z

PLoS genetics 20140213 2

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common ...[more]

PMID: 24550738

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Project description:Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5×10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies across three biobanks (PMBB, UKB, AOU) including 27,208 individuals with HF and 349,126 without uncover exome-wide significant (p < 3.15×10-6) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN, MYBPC3, FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, and is lower than heritability attributable to common variants (4.3%, 95% CI 3.9-4.7%) which is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

Dataset Information

Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

Publications

Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

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