Linkage studies in common obesity

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The number of genome wide scans conducted in human populations has risen steadily over the last few years. Whilst many of these studies have yielded somewhat equivocal results, often due to limited sample size, there are now several studies showing evidence of linkage (LOD [likelihood of odds ratio] scores greater than 2.5) and these are discussed in this section. For a comprehensive list of all linkage studies performed see Human Obesity Gene Map (link to www.obesite.chaire.ulaval.ca/ genemap.html).

To date, significant linkage results for obesity-related phenotypes have been published from a wide variety of human populations and importantly several studies have now replicated human obesity quantitative trait loci (QTLs) across different ethnic groups. To this extent there is now an emerging pattern with evidence that several major genes contribute to the variation in obesity related phenotypes in humans. Interestingly, not only are these linkage signals supported by significant LOD scores but many of these areas contain strong positional candidate genes for obesity related phenotypes.

At present, the strongest evidence for a QTL influencing obesity-related phenotypes in humans comes from the San Antonio Family Heart Study (SAFHS) with a Log Odds Ratio (LOD) score of 7.5 for serum leptin levels on chromosome 2 (Comuzzie et al., 1997). This study used a sample of 459 Mexican-Americans distributed in ten families. In addition, in this population significant linkage has also been detected on chromosome 8 with both leptin (LOD = 3.1) (Martin et al., 2002) and BMI (LOD = 3.2) (Mitchell etal., 1999), as well as on chromosome 17 (LOD = 3.2) for BMI (Comuzzie, 2002).

The chromosome 2 QTL localizes very near the POMC locus, which encodes pro-opiomelanocor-tin. Hixson and colleagues detected significant association (P — 0.001) between molecular variation in the POMC locus and variation in serum leptin levels among Mexican-Americans (Hixson et al., 1999). The region containing the QTL on chromosome 8 contains the b-3-adrenergic receptor (ADRB3 gene), a strong candidate previously identified on the basis of its known activity.

The Pima Indian community of Arizona, which has a particularly high prevalence of obesity, were among the first to be examined in a genome-wide scan. Currently, QTLs have been detected on chromosomes 1,3,6,11,18 and 20 with LOD scores ranging from 2 to 3.6. The strongest evidence for a QTL in the Pima Indians is on chromosome 11 (approximately 11q21-q24) with a LOD score of 3.6 for BMI (Hanson et al., 1998). Additional obesity-related phenotypes, including percent body fat (LOD — 2.8) and 24-hour energy expenditure (LOD — 2.0) have also yielded linkage signals in this region in the Pima. There is evidence for a QTL located on chromosome 20 (approximately 20q11.2) for 24-hour respiratory quotient (24RQ) with a LOD score of 3.0. Norman et al. detected a LOD score of 2.3 on chromosome 18 (18q21) for percent body fat and a LOD score of 2.8 for 24RQ

Several groups have now published the results from genome screens conducted in populations of Western European (White) ancestry. The largest of these studies has been based on a collection of nuclear families collected from the mid-western region of the United States with 2209 individuals from 507 families (Kissebah et al., 2000). Kissebah and colleagues detected a QTL on chromosome 3 (3q27) strongly linked to a number of traits related to obesity (including BMI, waist circumference and fasting insulin) with LOD scores ranging from 2.4 to 3.5 (Kissebah et al., 2000). In addition, a second QTL influencing serum leptin levels was detected on chromosome 17 with a LOD score of 5.0. The region identified by the QTL on chromosome 3 contains several very promising positional candidate genes (e.g. adiponectin, GLUT2, PI3K), as does the region containing the chromosome 17 QTL (e.g. GLUT4 and PPARa).

Hager and colleagues have published the results of a genome scan for obesity as a discrete trait (defined as a BMI >27) in affected French sib pairs (Hager etal., 1998). Significant evidence of linkage on chromosome 10 (10p) with a LOD score of 4.9 was found. The same locus showed suggestive linkage (LOD — 2.7) for BMI-adjusted leptin in an Old Order Amish population. The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on chromosome 10p11-12. In a recent French case-control study of 575 morbidly obese and 646 control subjects, a protective haplotype including the most frequent alleles of two single nucleotide polymorphisms (SNPs) and an at-risk SNP for morbid obesity were identified (Boutin et al., 2003).

In White French sample populations, evidence of linkage to variation in serum leptin levels on chromosomes 2 and 5 has been reported. In a subsequent study of French families with Type 2 diabetes, Vionnet and colleagues reported a significant linkage signal on chromosome 3 (3q27-qter) for diabetes and glucose tolerance (Vionnet et al.,

2000) and evidence of linkage to diabetes on chromosomes 2 and 20.

In a genome scan of Finnish obese nuclear families, using an affected sib pair design, Ohman and colleagues identified a susceptibility locus on chromosome Xq24 (maximum likelihood score (MLS) 3.14) (Ohman etal., 2000). By fine mapping, they reduced the linkage region to 4Mb and have identified three functional candidate genes, AGTR2, SLC6A14, and SLC25A5. Significant evidence for association was observed for a SNP in the SLC6A14 gene region and also with SNP haplotypes in the same gene. A significant difference in allele frequency was observed between obese and nonobese individuals in two independently ascertained Scandinavian cohorts (Suviolahti et al., 2003).

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