Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Saunders, EJ (Author) Other; Dadaev, T (Author) Other; Leongamornlert, DA (Author) Other; Jugurnauth Little, S (Author) Other; Tymrakiewicz, M (Author) Other; Wiklund, F (Author) Other; Al Olama, AA (Author) Other; Benlloch, S (Author) Other; Neal, DE (Author) Other; Hamdy, FC (Author) Other; Donovan, JL (Author) Other; Giles, GG (Author) Other; Severi, G (Author) Other; Gronberg, H (Author) Other; Aly, M (Author) Other; Haiman, CA (Author) Other; Schumacher, F (Author) Other; Henderson, BE (Author) Other; Lindstrom, S (Author) Other; Kraft, P (Author) Other; Hunter, DJ (Author) Other; Gapstur, S (Author) Other; Chanock, S (Author) Other; Berndt, SI (Author) Other; Albanes, D (Author) Other; Andriole, G (Author) Other; Schleutker, J (Author) Other; Weischer, M (Author) Other; Nordestgaard, BG (Author) Other; Canzian, F (Author) Other; Campa, D (Author) Other; Riboli, E (Author) Other; Key, TJ (Author) Other; Travis, RC (Author) Other; Ingles, SA (Author) Other; John, EM (Author) Other; Hayes, RB (Author) Other; Pharoah, P (Author) Other; Khaw, KT (Author) Other; Stanford, JL (Author) Other; Ostrander, EA (Author) Other; Signorello, LB (Author) Other; Thibodeau, SN (Author) Other; Schaid, D (Author) Other; Maier, C (Author) Other; Kibel, AS (Author) Other; Cybulski, C (Author) Other; Cannon Albright, L (Author) Other; Brenner, H (Author) Other; Park, JY (Author) Other; Kaneva, R (Author) Other; Batra, J (Author) Other; Clements, JA (Author) Other; Manuel R Teixeira (Author) ICBAS; Xu, JF (Author) Other; Mikropoulos, C (Author) Other; Goh, C (Author) Other; Govindasami, K (Author) Other; Guy, M (Author) Other; Wilkinson, RA (Author) Other; Sawyer, EJ (Author) Other; Morgan, A (Author) Other; Easton, DF (Author) Other; Muir, K (Author) Other; Eeles, RA (Author) Other; Kote Jarai, Z (Author) Other

Journal

Title: Plos Genetics

Vol. 10

ISSN: 1553-7390

Publisher: Public Library of Science

Indexing

ISI Web of Knowledge - 31 Citations

Scopus - 29 Citations

Other information

Authenticus ID: P-009-D70

DOI: 10.1371/journal.pgen.1004129

Abstract (EN): Author Summary Genome-wide association studies (GWAS) have identified numerous low penetrance disease susceptibility variants, yet few causal alleles have been unambiguously identified. The underlying causal variants are expected to be predominantly common; however synthetic associations with rare, higher penetrance variants have been hypothesised though not yet observed. Here, we report detection of a novel common, low penetrance prostate cancer association at the HOXB locus at ch17q and show that this signal can actually be attributed to a previously identified rare, moderate penetrance coding variant (G84E) in HOXB13. This study therefore provides the first experimental evidence for the existence of synthetic associations in cancer and shows that where GWAS signals arise through this phenomenon, risk predictions derived using the tag SNP would substantially underestimate the relative risk conferred and overestimate the number of carriers of the causal variant. Synthetic associations at GWAS signals could therefore account for a proportion of the missing heritability of complex diseases. 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 = 2.62x10(-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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8