Detailed Investigation of the Role of Common and Low-Frequency WFS1 Variants in Type 2 Diabetes Risk
Open Access
- 12 December 2009
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 59 (3), 741-746
- https://doi.org/10.2337/db09-0920
Abstract
OBJECTIVE Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects. RESULTS Of 31 tagging SNPs, the strongest associated was the previously untested 3′ untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 × 10−7 on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] 100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.Keywords
This publication has 26 references indexed in Scilit:
- Statistical independence of the colocalized association signals for type 1 diabetes and RPS26 gene expression on chromosome 12q13Biostatistics, 2008
- Common and rare variants in multifactorial susceptibility to common diseasesNature Genetics, 2008
- Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populationsDiabetologia, 2007
- Common variants in WFS1 confer risk of type 2 diabetesNature Genetics, 2007
- WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulumFEBS Letters, 2006
- The Exeter Family Study of Childhood Health (EFSOCH): study protocol and methodologyPaediatric and Perinatal Epidemiology, 2006
- Genome-Wide Associations of Gene Expression Variation in HumansPLoS Genetics, 2005
- Direct analysis of unphased SNP genotype data in population-based association studies via Bayesian partition modelling of haplotypesGenetic Epidemiology, 2005
- TrueInternational Journal of Obesity, 1999
- Diabetes mellitus, diabetes insipidus, and optic atrophy. An autosomal recessive syndrome?Journal of Medical Genetics, 1977