© 2010 by the American Diabetes Association.
Detailed Investigation of the Role of Common and Low-Frequency WFS1 Variants in Type 2 Diabetes Risk
1Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, U.K.;
2Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.;
3Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, U.K.;
4Section for Nutritional Research, Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden;
5Section for Family Medicine, Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden;
6Department of Medicine, Metabolism, Diabetes and Lipid Research Division, Washington University School of Medicine, Saint Louis, Missouri;
7Department of Internal Medicine, Metabolism, Diabetes and Lipid Research Division, Washington University School of Medicine, Saint Louis, Missouri;
8Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.;
9Endocrine and Metabolism Service, The Hadassah Hebrew University Medical Center, Jerusalem, Israel;
10Section for Medicine, Department of Public Health & Clinical Medicine, Genetic Epidemiology & Clinical Research Group, Umeå University Hospital, Umeå, Sweden;
11Section for Nutritional Research, Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden;
12Oxford Centre for Diabetes Endocrinology & Metabolism, Churchill Hospital, University of Oxford, Oxford, U.K.;
13Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Headington, Oxford, U.K.;
14Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, U.K.;
15Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K.
Received June 22, 2009; Accepted December 10, 2009.
The post genome-wide association study era presents several challenges. These include fine-mapping association signals to genes and/or variants within the genomic regions of interest, assessing the impact of low frequency variants (not tagged in previous association studies) on diseases/traits, and understanding the functional mechanisms behind genetic associations.
encodes wolframin (1
), an endoplasmic reticulum (ER) membrane protein with a role in ER calcium homeostasis (3
) and in the ER stress response (6
). Loss-of-function mutations in WFS1
cause Wolfram syndrome (MIM 222300), which includes young onset nonautoimmune insulin-dependent diabetes (8
). Common single nucleotide polymorphisms (SNPs) at WFS1
have recently been shown to be reproducibly associated with type 2 diabetes risk in white European populations (9
). However, the strongest associated SNP, rs10010131, is intronic and is not associated with WFS1
expression in HapMap lymphoblastoid cell lines (12
), suggesting that it is tagging a causal variant(s).
Given the impact of rare and common WFS1
variants on Mendelian and common forms of diabetes, respectively, WFS1
is an excellent candidate gene in which to look for low frequency variants with intermediate effects on diabetes risk. Furthermore, anecdotal evidence suggests increased type 2 diabetes susceptibility in obligate carriers of Wolfram syndrome mutations (13
We aimed to refine the association between WFS1 common variants and type 2 diabetes by sequencing exons, splice junctions, and conserved intragenic and upstream noncoding regions in a subset of case (n = 24) and control (n = 68) subjects from the Cambridgeshire case-control study. We used these data to select tagging SNPs to capture common (minor allele frequency [MAF] >0.05) and nonsynonymous variants and genotyped these tagging SNPs in two U.K. case-control studies (total 959 case and 1,386 control subjects). Replication studies were conducted in four additional studies: two U.K., one Swedish, and one Ashkenazi (total 3,753 type 2 diabetic case and 4,198 control subjects). We also aimed to test for the presence of independent type 2 diabetes association signals from low-frequency (MAF <0.05) putative functional WFS1 variants by sequencing 1,235 type 2 diabetic case and 1,668 control subjects from two U.K. case-control studies.