Sequencing and association analysis of the type 1 diabetes - linked region on chromosome 10p12-q11.
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Smink, Luc J
Smyth, Deborah J
Lowe, Christopher Eric
Godfrey, Lisa M
Lam, Alex C
Walker, Neil M
Twells, Rebecca CJ
Barratt, Bryan J
Wright, Charmain L
Todd, John Andrew
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Nejentsev, S., Smink, L. J., Smyth, D. J., Bailey, R., Lowe, C. E., Payne, F., Masters, J., et al. (2007). Sequencing and association analysis of the type 1 diabetes - linked region on chromosome 10p12-q11.. https://doi.org/10.1186/1471-2156-8-24
Background: In an effort to locate susceptibility genes for type I diabetes (TID) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with TID. Results: Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with TID. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex TID families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05-0.0026), located near the PAPDI gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the TID families. We also tested 13 polymorphisms in the PAPDI gene and in five other loci in 1,612 TID patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPDI showed nominal evidence of association in both TID families and in the case-control sample (P = 0.037 and 0.03, respectively). Conclusion: We conclude that polymorphisms in the CREM and SDFI genes have no major effect on TID. The weak TID association that we detected in the association scan near the PAPDI gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.
External DOI: https://doi.org/10.1186/1471-2156-8-24
This record's URL: http://www.dspace.cam.ac.uk/handle/1810/238030
Rights Holder: Nejentsev et al.; licensee BioMed Central Ltd.