Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes.
The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K., only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.
Frayling
T M
TM
Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, UK.
Walker
M
M
McCarthy
M I
MI
Evans
J C
JC
Allen
L I
LI
Lynn
S
S
Ayres
S
S
Millauer
B
B
Turner
C
C
Turner
R C
RC
Sampson
M J
MJ
Hitman
G A
GA
Ellard
S
S
Hattersley
A T
AT
D000328:Adult; D001323:Autoantibodies / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D005060:Europe; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009679:Nuclear Family; D015995:Prevalence; D012306:Risk; D006113:United Kingdom; D044465:White People / Q000235:genetics*
D001323:Autoantibodies; D005968:Glutamate Decarboxylase