This article is part of the supplement: Beyond the Genome 2011

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An unusual suspect: an uncommon human-specific synonymous coding variant within the UGT1A6 gene explains a GWAS signal and protects against bladder cancer

Wei Tang1, Yi-Ping Fu1, Jonine D Figueroa2, Núria Malats3, Montserrat Garcia-Closas24, Nilanjan Chatterjee2, Manolis Kogevinas5678, Dalsu Baris2, Michael Thun9, Jennifer L Hall10, Immaculata De Vivo11, Demetrius Albanes2, Patricia Porter-Gill1, Mark P Purdue2, Laurie Burdett12, Luyang Liu1, Amy Hutchinson12, Timothy Myers12, Adonina Tardón137, Consol Serra14, Alfredo Carrato15, Reina Garcia-Closas16, Josep Lloreta17, Alison Johnson18, Molly Schwenn19, Margaret R Karagas20, Alan Schned21, Amanda Black2, Eric J Jacobs9, W Ryan Diver9, Susan M Gapstur9, Jarmo Virtamo22, David J Hunter23, Joseph F Fraumeni2, Stephen J Chanock1, Debra T Silverman2, Nathaniel Rothman2 and Ludmila Prokunina-Olsson1*

  • * Corresponding author: Ludmila Prokunina-Olsson

Author Affiliations

1 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA

2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA

3 Spanish National Cancer Research Centre, Madrid 28029, Spain

4 Division of Genetics and Epidemiology, Institute of Cancer Research, London SW7 3RP, UK

5 Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain

6 Municipal Institute of Medical Research, Barcelona 08003, Spain

7 CIBER Epidemiología y Salud (CIBERESP), Barcelona 08003, Spain

8 National School of Public Health, Athens 11521, Greece

9 Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA

10 Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA

11 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA

12 Core Genotype Facility, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702, USA

13 Universidad de Oviedo, Oviedo 33003, Spain

14 Universitat Pompeu Fabra, Barcelona 08002, Spain

15 Ramón y Cajal University Hospital, Madrid 28034, Spain

16 Unidad de Investigación, Hospital Universitario de Canarias, La Laguna 38320, Spain

17 Hospital del Mar-Institut Municipal d’Investigació Mèdica (IMIM), Universitat Pompeu Fabra, Barcelona 08003, Spain

18 Vermont Cancer Registry, Burlington, VT 05401, USA

19 Maine Cancer Registry, Augusta, ME 04333, USA

20 Dartmouth Medical School, Hanover, NH 03755, USA

21 Department of Urology, Washington University School of Medicine, St. Louis, MO 63110, USA

22 National Institute for Health and Welfare, Helsinki 00271, Finland

23 Department of Epidemiology, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA

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Genome Biology 2011, 12(Suppl 1):P19  doi:10.1186/gb-2011-12-s1-p19

The electronic version of this article is the complete one and can be found online at:

Published:19 September 2011

© 2011 Tang et al; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


A recent genome-wide association study (GWAS) of bladder cancer identified a single nucleotide polymorphism (SNP), rs11892031, within the UGT1A gene cluster on chromosome 2q37.1, as a novel risk factor. The UGT1A locus encodes nine UGT proteins, which belong to the phase II cellular detoxification system. UGTs are functionally important for the detoxification of aromatic amines, which are found in industrial chemicals and tobacco smoke and are known risk factors for bladder cancer. The UGT-encoding genes have exons 2 to 5 in common but have different first exons, which define the enzymatic activity and substrate specificity of the gene products.

Methods and results

We sequenced all nine highly similar alternative first exons for the UGT-encoding genes of up to 2,000 individuals. We identified 26 known nonsynonymous and 17 known synonymous coding variants but no novel variants. Imputation based on the GWAS dataset, a combined reference panel of HapMap 3 and the 1000 Genomes Project, and a subset of GWAS samples genotyped for all of the identified coding variants generated data for 1,170 SNPs within the whole UGT1A region. Of these markers, the strongest association was detected for an uncommon protective genetic variant that explained the original GWAS signal (odds ratio (OR) = 0.55, 95% confidence interval (CI) = 0.44 to 0.69, P = 3.3 × 10–7 in 4,035 cases and 5, 284 controls; D′ = 0.96, r2 = 0.23 with rs11892031). No residual association in this region was detected after adjustment for this SNP. A typical genetic variant identified by GWAS for a common disease is expected to be a common allele (>10% minor allele frequency) that increases the disease risk. We show that the novel associated variant is an uncommon protective allele (1.14% in cases and 2.5% in controls). Interestingly, the risk allele (G) is conserved in 33 species, whereas the protective allele (T) is a human-specific variant. Even though this SNP is a synonymous coding variant, we show its association with quantitative mRNA expression of a specific functional splicing form of UGT1A6, probably through an exonic splicing enhancer.


This study exemplifies that uncommon protective genetic variants are unusual suspects that may play important but underestimated functional roles in complex traits.