Despite recent advances in the molecular genetics of type 2 diabetes, the majority of susceptibility genes in humans remain to be identified. We therefore conducted a 10-cM genomewide search (401 microsatellite markers) for type 2 diabetes-related traits in 637 members of 143 French pedigrees ascertained through multiple diabetic siblings, to map such genes in the white population. Nonparametric two-point and multipoint linkage analyzes-using the MAPMAKER-SIBS (MLS) and MAXIMUM-BINOMIAL-LIKELIHOOD (MLB) programs for autosomal markers and the ASPEX program for chromosome X markers-were performed with six diabetic phenotypes: diabetes and diabetes or glucose intolerance (GI), as well as with each of the two phenotypes associated with normal body weight (body-mass index<27 kg/m(2)) or early age at diagnosis (<45 years). In a second step, high-resolution genetic mapping ( approximately 2 cM) was performed in regions on chromosomes 1 and 3 loci showing the strongest linkage to diabetic traits. We found evidence for linkage with diabetes or GI diagnosed at age <45 years in 92 affected sib pairs from 55 families at the D3S1580 locus on chromosome 3q27-qter using MAPMAKER-SIBS (MLS = 4.67, P=.000004), supported by the MLB statistic (MLB-LOD=3.43, P=.00003). We also found suggestive linkage between the lean diabetic status and markers APOA2-D1S484 (MLS = 3. 04, P=.00018; MLB-LOD=2.99, P=.00010) on chromosome 1q21-q24. Several other chromosomal regions showed indication of linkage with diabetic traits, including markers on chromosome 2p21-p16, 10q26, 20p, and 20q. These results (a) showed evidence for a novel susceptibility locus for type 2 diabetes in French whites on chromosome 3q27-qter and (b) confirmed the previously reported diabetes-susceptibility locus on chromosome 1q21-q24. Saturation on both chromosomes narrowed the regions of interest down to an interval of <7 cM.

Obesity, a common multifactorial disorder, is a major risk factor for type 2 diabetes, hypertension and coronary heart disease (CHD). According to the definition of the World Health Organization (WHO), approximately 6-10% of the population in Westernized countries are considered obese. Epidemiological studies have shown that 30-70% of the variation in body weight may be attributable to genetic factors. To date, two genome-wide scans using different obesity-related quantitative traits have provided candidate regions for obesity. We have undertaken a genome-wide scan in affected sibpairs to identify chromosomal regions linked to obesity in a collection of French families. Model-free multipoint linkage analyses revealed evidence for linkage to a region on chromosome 10p (MLS=4.85). Two further loci on chromosomes 5cen-q and 2p showed suggestive evidence for linkage of serum leptin levels in a genome-wide context. The peak on chromosome 2 coincided with the region containing the gene (POMC) encoding pro-opiomelanocortin, a locus previously linked to leptin levels and fat mass in a Mexican-American population and shown to be mutated in obese humans. Our results suggest that there is a major gene on chromosome 10p implicated in the development of human obesity, and the existence of two further loci influencing leptin levels.

Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of North-Eastern Indian origin including 535 individuals. Families were ascertained through a proband with CHD before 52 years of age and additional sibs with myocardial infarction (MI) or T2DM. Model-free two-point and multipoint linkage analysis were performed using the Mapmarker-Sibs (MLS) and maximum-likelihood-binomial (MLB) programs for autosomal markers and the Aspex program for chromosome X markers. In a second step, additional markers were studied to increase the genetic map density in three regions on chromosomes 3, 8 and 16 where initial indication for linkage was found. Our data show suggestive linkage with CHD on chromosome 16p13-pter with the MLS statistics at 8.69 cM (LOD = 3.06, P = 0.00017) which partially overlaps with a high pressure (HBP) peak. At the same locus, a nominal indication for linkage with T2DM was found in 35 large T2DM Pondicherian families also having Indian origin. With respect to region 8q23, we found suggestive linkage with T2DM (LOD = 2.55, P = 0.00058) as well as with HBP. On 3q27, we replicated previous indication for linkage found in Caucasians (for the metabolic syndrome and for diabetes) according to the categorized trait for CHD and MI with the MLB statistics (LOD = 2.13, P = 0.0009). The genome scan also revealed nominal evidence of linkage with CHD on 10q23 (LOD = 2.06, P = 0.00188). Interestingly, we detected in the same region overlapping linkages with three QTLs: age of onset of CHD (LOD = 2.03), HDL cholesterol (LOD = 1.48) and LDL/HDL ratio (LOD = 1.34). Ordered-subset analysis based on family body mass index ranking replicated finding on 2q37 for T2DM (at Calpain 10 locus). These results show the first evidence for susceptibility loci that predispose to CHD, T2DM and HBP in the context of the metabolic syndrome.