The Finland–United States Investigation of Non–Insulin‐Dependent Diabetes Mellitus Genetics (FUSION) Study. II. An Autosomal Genome Scan for Diabetes‐Related Quantitative‐Trait Loci

Abstract

Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting Cpeptide/glucose: maximum LOD score [MLS] p 3.13 at 53.0 cM) and 13 (body-mass index: MLS p 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS p 3.11 at 21.0 cM), 13 (2-h insulin: MLS p 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS p 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS p 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS p 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS p 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.

Heritability of fasting glucose levels in a young genetically isolated population

“…In the Finnish population, where the heritability of fasting glucose was estimated to be 8.4% after correction for ascertainment, elevated fasting glucose was suggestively linked to chromosome 3 [19]. In another population of European Caucasian descent, the heritability of fasting glucose was 34%, but only suggestive linkage to chromosome 10q and weak linkage to 1q were found [20].…”

Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

“…These difficulties are encountered in all cross-sectional studies. The overlapping regions of linkage observed for the diabetes-related phenotypes in Pima [23] and Finnish [26] families, and the Framingham Offspring [6] and Heart Studies [25], support the existence of genes affecting fasting serum insulin concentrations on chromosomes 19 and 5 and fasting serum glucose on chromosome 13.…”

“…Linkage with fasting glucose, and combined fasting and non-fasting glucose, was detected on chromosome 5 at 0 cM in the Framingham Offspring Study (LOD 1.09) [6], and Framingham Heart Study (LOD 1.65) [25]. The HyperGEN fasting serum glucose scan loci on chromosome 13 are near reported loci for related phenotypes in 580 Finnish families from the FUSION Study [26], i.e., 2-h insulin (LOD 2.86 at 65 cM) and insulin secretion (insulin/ glucose) (LOD 1.37 at 62 cM), and loci for type 2 diabetes in AAs with earlier age at diagnosis (p<0.006 at 76 cM) [27] and Japanese families (LOD 0.94, 79 cM) [28]. Linkage for these phenotypes resides within, or near, the peaks where we found evidence for linkage to fasting insulin (chromosomes 19 and 5) and fasting glucose (5 and 13) in the univariate analyses.…”

Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population

“…In Japanese people, it was reported to substantially overlap with that in Mexican Americans [6,13] and with that reported in the American Diabetes Association's Genetics of NIDDM study in Mexican Americans [14]. These results in Mexican Americans were replicated in Pima Indians [15] and Finnish families [16] (Electronic supplementary material [ESM] Table 1). …”

“…In this study, we selected a target region on chromosome 3p24.3-22.1 that corresponds to 20.4 Mb based on replicated linkage for type 2 diabetes or its related traits [6,[12][13][14][15][16]. We adopted a two-step association test using 1,762 Japanese subjects to reduce the time and cost of genotyping.…”