A German genome-wide linkage scan for type 2 diabetes supports the existence of a metabolic syndrome locus on chromosome 1p36.13 and a type 2 diabetes locus on chromosome 16p12.2

Abstract

The aim was to identify type 2 diabetes susceptibility regions in 250 German families. We conducted a genome-wide linkage scan using 439 short tandem repeat polymorphisms at an average resolution of 7.76 +/- 3.80 cM (Marshfield). In an affected-only-design (affected sib pairs), we performed nonparametric multipoint linkage analyses. Conditional analyses were applied where linkage signals were found in the baseline analyses. We identified two loci with nominal evidence for linkage on chromosomes 1p36.13 and 16p12.2 (D1S3669, 37.05 cM, logarithmic odds ratio [LOD] = 1.49, p = 0.004; D16S403, 43.89 cM, LOD = 1.85, p = 0.002). D16S403 crossed the empirically obtained threshold of genome-wide suggestive significance of LOD = 1.51. Positive findings in those regions have been reported by the following other linkage studies on: (1) symptomatic/clinical gall bladder disease with type 2 diabetes in Mexican Americans from the San Antonio Family Diabetes/Gallbladder Study (LOD = 3.7, D1S1597-D1S407, 29.93-33.75 cM); (2) body size-adiposity in another Mexican American population (D1S1597, LOD = 2.53, 29.93 cM); (3) lipid abnormalities (LOD = 3.1, D1S2826-D1S513, 41.92-60.01 cM); and (4) hypertension in Australian sib pairs (LOD = 3.1, D1S2834-D1S2728, 31.02-33.75 cM); as well as (5) a meta-analysis of four European type 2 diabetes-related genome scans (LOD = 1.09, D16S412, 42.81 cM). In linkage analyses conditional on evidence for linkage at D16S403 we identified a LOD increase (Delta LOD) of 1.55 (p = 0.0075) at D17S2180. Similar conditioning on D17S2180 revealed evidence for interaction with D1S3669 (Delta LOD = 1.67, p = 0.0055), D16S403 (Delta LOD = 1.48, p = 0.0091) and another locus on chromosome 1 where several genome scans have reported evidence for linkage ( approximately 200 cM, Delta LOD = 1.60, p = 0.0066). Our results and the findings of other studies are consistent with the presence of a locus for a complex metabolic syndrome on chromosome 1p36.13.