Linkage Disequilibrium Mapping of the Replicated Type 2 Diabetes Linkage Signal on Chromosome 1q

Prokopenko, I., Zeggini, E., Hanson, R. L., Mitchell, B. D., Rayner, N. W., Akan, P., Baier, L., Das, S. K., Elliott, K. S., Fu, M., Frayling, T. M., Groves, C. J., Gwilliam, R., Scott, L. J., Voight, B. F., Hattersley, A. T., Hu, C., Morris, A. D., Ng, M., Palmer, C. N. A., Tello-Ruiz, M., Vaxillaire, M., Wang, C. R., Stein, L. D., Chan, J., Jia, W. P., Froguel, P., Elbein, S. C., Deloukas, P., Bogardus, C., Shuldiner, A. R., McCarthy, M. I. (2009) Linkage Disequilibrium Mapping of the Replicated Type 2 Diabetes Linkage Signal on Chromosome 1q. Diabetes, 58 (7). pp. 1704-1709. ISSN 0012-1797

URL: http://www.ncbi.nlm.nih.gov/pubmed/19389826
DOI: 10.2337/db09-0081

Abstract

OBJECTIVE-Linkage of the chromosome 1q21-25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal. RESEARCH DESIGN AND METHODS-In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate similar to 80% coverage of common variation across the region (r(2) > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in similar to 8,500 case subjects and 12,400 control subjects. RESULTS-Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21-1.571, P = 1.4 x 10(-6), in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18-1.761, P = 1.0 x 10(-5), under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status. CONCLUSIONS-Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance. Diabetes 58:1704-1709, 2009

Item Type: Paper
Uncontrolled Keywords: GENOME-WIDE ASSOCIATION NUCLEAR FACTOR-4-ALPHA GENE GK RAT SUSCEPTIBILITY LOCI VARIANTS RISK POPULATION DISEASES SAMPLES
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > nutritional and metabolic diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosome
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function > chromosome

diseases & disorders > nutritional and metabolic diseases > diabetes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > single nucleotide polymorphism
CSHL Authors:
Communities: CSHL labs > Stein lab
Depositing User: Matt Covey
Date Deposited: 20 Feb 2013 22:16
Last Modified: 20 Feb 2013 22:16
PMCID: PMC2699860
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27405

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