Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11.
BACKGROUND
In an effort to locate susceptibility genes for type 1 diabetes (T1D) 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 T1D.


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 T1D. 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 T1D 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 PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively).


CONCLUSIONS
We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.
Nejentsev
Sergey
S
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. sergey.nejentsev@cimr.cam.ac.uk
Smink
Luc J
LJ
Smyth
Deborah
D
Bailey
Rebecca
R
Lowe
Christopher E
CE
Payne
Felicity
F
Masters
Jennifer
J
Godfrey
Lisa
L
Lam
Alex
A
Burren
Oliver
O
Stevens
Helen
H
Nutland
Sarah
S
Walker
Neil M
NM
Smith
Anne
A
Twells
Rebecca
R
Barratt
Bryan J
BJ
Wright
Charmain
C
French
Lisa
L
Chen
Yuan
Y
Deloukas
Panagiotis
P
Rogers
Jane
J
Dunham
Ian
I
Todd
John A
JA
D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide
D017931:DNA Primers; D005819:Genetic Markers