Advanced

Type 1 Diabetes: Evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families.

Concannon, P; Erlich, HA; Julier, C; Morahan, G; Nerup, J; Pociot, F; Todd, JA; Rich, SS; Type 1 Diabetes Genetics Consortium, the and Carlson, Joyce LU (2005) In Diabetes 54. p.2995-3001
Abstract
Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [{lambda}S] ~ 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific {lambda}S ~ 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] ~ 1.9), CTLA4 (chromosome 2q33, allelic OR ~ 1.2), and PTPN22 (chromosome 1p13, allelic OR ~ 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously... (More)
Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [{lambda}S] ~ 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific {lambda}S ~ 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] ~ 1.9), CTLA4 (chromosome 2q33, allelic OR ~ 1.2), and PTPN22 (chromosome 1p13, allelic OR ~ 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 x 10–52), nine non–HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10–4). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect ({lambda}S ≥ 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
54
pages
2995 - 3001
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:25844441709
ISSN
1939-327X
language
English
LU publication?
yes
id
d511545c-f949-4a32-983a-1267c98b26a0 (old id 1133981)
alternative location
http://diabetes.diabetesjournals.org/cgi/content/full/54/10/2995#SEC4
date added to LUP
2008-06-19 09:20:45
date last changed
2017-10-22 04:38:53
@article{d511545c-f949-4a32-983a-1267c98b26a0,
  abstract     = {Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [{lambda}S] ~ 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific {lambda}S ~ 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] ~ 1.9), CTLA4 (chromosome 2q33, allelic OR ~ 1.2), and PTPN22 (chromosome 1p13, allelic OR ~ 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 x 10–52), nine non–HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P &lt; 0.01), including three at (or near) genome-wide significance (P &lt; 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P &lt; 10–4). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect ({lambda}S ≥ 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations.},
  author       = {Concannon, P and Erlich, HA and Julier, C and Morahan, G and Nerup, J and Pociot, F and Todd, JA and Rich, SS and Type 1 Diabetes Genetics Consortium, the and Carlson, Joyce},
  issn         = {1939-327X},
  language     = {eng},
  pages        = {2995--3001},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Type 1 Diabetes: Evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families.},
  volume       = {54},
  year         = {2005},
}