A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians.

Abstract

Considerable evidence supports a major inherited component of type 2 diabetes. We initially conducted a genome-wide scan with 440 microsatellite markers at 10-cM intervals in 19 multigenerational families of Northern European ancestry with at least two diabetic siblings. Initial two-point analyses of these families directed marker typing of 23 additional families. Subsequently, all available marker data on the total of 42 families were analyzed using both parametric and nonparametric multipoint methods to test for linkage to type 2 diabetes. One locus on chromosome 1q21-1q23 met genome-wide criteria for significant linkage under a model of recessive inheritance with a common diabetes allele (logarithm of odds [LOD] = 4.295). Both pedigree-based nonparametric linkage (NPL) analysis and affected sib pair (MAPMAKER/SIBS) nonparametric methods also showed the highest genome-wide scores at this region, near markers CRP and APOA2, but failed to meet levels of genome-wide significance. The risk of type 2 diabetes to siblings of a diabetic person when compared with the population (lambdaS) was estimated from MAPMAKER/SIBS to be 2.8 in these 42 families. Simulation studies using study data confirmed a genome-wide significance level of P<0.05 (95% CI 0.005-0.0466). However, analysis of 20 similarly ascertained but smaller families failed to confirm this linkage. The LOD score with 50% heterogeneity for all 62 families considered together was only 2.25, with an estimated lambdaS of 1.87. Our data suggest a novel diabetes susceptibility locus near APOA2 on chromosome 1 in a region with many transcribed genes.

Identification of differentially expressed genes in skeletal muscle of non-diabetic insulin-resistant and insulin-sensitive Pima Indians by differential display PCR

“…Nevertheless, we cannot exclude the possibility that polymorphisms in the ATP1A2 gene might be the primary cause for insulin resistance. This gene maps to chromosome 1q21-23, a region previously reported to be linked to insulin resistance and Type 2 diabetes in Pima Indians [28], French population [29], and Utah Caucasians [30]. Thus, the ATP1A2 gene can still be considered as a candidate susceptibility gene for insulin resistance.…”

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

“…Thus, although, because of clearly defined diagnostic criteria (National Diabetes Data Group 1979;World Health Organization 1985), individuals can be identified as having type 2 diabetes, not all individuals who eventually develop type 2 diabetes follow the same path toward disease, nor will they follow the same progression toward disease complications. These complex features may account for why, despite the large number of groups performing genomic scans for type 2 diabetes (Hanis et al 1996;Mahtani et al 1996;Hanson et al 1998;Imperatore et al 1998;Pratley et al 1998;Duggirala et al 1999;Elbein et al 1999;Ghosh et al 1999;Ehm et al 2000), there have been, until recently, no published reports of a successful cloning and identification of a major susceptibility gene. However, recently the chromosome 2 locus linked to type 2 diabetes in Mexican Americans, also known as "NIDDM1" (Hanis et al 1996), has been cloned and identified as calpain-10, a calpain-like cysteine protease (Horikawa et al 2000).…”

“…Although evidence has been reported for chromosomal regions that may contain type 2 diabetes-susceptibility genes, until recently only genes for specific subtypes of type 2 diabetes, such as maturity-onset diabetes of the young (MODY), have appeared in the literature (Bell et al 1991;Vaxillaire et al 1995;Horikawa et al 1997;Stoffers et al 1997). These relatively rare subtypes of type 2 diabetes have been determined to be monogenic in nature, and multiple studies suggest that these genes play, at most, a minor role in genetic susceptibility for the more general form(s) of type 2 diabetes (Hanis et al 1996;Mahtani et al 1996;Elbein et al 1999). Recently, the chromosome 2 locus linked to type 2 diabetes in Mexican Americans (Hanis et al 1996) has been cloned and identified as calpain-10 (Horikawa et al 2000).…”

“…Several groups have performed genome scans for type 2 diabetes, in attempts to identify disease-susceptibility loci (Hanis et al 1996;Mahtani et al 1996;Hanson et al 1998;Imperatore et al 1998;Pratley et al 1998;Duggirala et al 1999;Elbein et al 1999;Ghosh et al 1999;Ehm et al 2000). Although evidence has been reported for chromosomal regions that may contain type 2 diabetes-susceptibility genes, until recently only genes for specific subtypes of type 2 diabetes, such as maturity-onset diabetes of the young (MODY), have appeared in the literature (Bell et al 1991;Vaxillaire et al 1995;Horikawa et al 1997;Stoffers et al 1997).…”

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

“…This was followed by SNPs-based fine-scale linkage disequilibrium (LD) and association mapping in the candidate region, supported by replicated linkage signals in Japanese and other multiple populations. In a number of candidate regions [5][6][7][8][9][10][11] for type 2 diabetes and its related traits, we selected the overlapping region on chromosome 3p24.3-22.1. This region showed nominal significance in linkage (maximum logarithm of the odds [lod] score=1.58) for type 2 diabetes in a Japanese population [12].…”