gms | German Medical Science

Aims: The molecular genetic analysis of obesity has led to the identification of a limited number of confirmed major genes. While such genes have a clear influence on the development of the phenotype, the underlying mutations are however infrequent and thus of minor clinical importance. The genetic predisposition to obesity must thus be polygenic; a number of such variants should be found in most obese subjects; however, these variants predisposing to obesity are also found in normal weight and even lean individuals.

Methods: High-throughput genotyping methods in up to 100,000 individuals. A polygene can only be identified and validated by statistical analyses. Each polygene makes only a small contribution to the development of obesity.

Results: The 103Ile allele of the Val103Ile SNP in the melanocortin-4-receptor gene (MC4R) was the first confirmed polygenetic variant with an influence on the body mass index (BMI); the more common Val103 allele is more frequent in obese individuals. The effect size of this allele on mean BMI is approximately -0.5 kg/m². The first genome-wide association study (GWAS) for obesity based on approx. 100,000 SNPs revealed association of a SNP in the proximity of the insulin-induced gene 2 (INSIG2) with obesity. The result was replicated in some but not all independent studies. SNP alleles in intron 1 of the ‘fat mass and obesity associated’ gene (FTO) confer the most relevant polygenic effect on obesity. In the first GWAS for extreme early onset obesity we substantiated that variation in FTO strongly contributes to early onset obesity. Recently, a total of 17 polygenic obesity genes were identified in large scaled GWAS approaches.

Conclusions: A small number of monogenic forms of obesity had been described; 17 polygenic loci were identified so far. In the near future more polygenes will be detected, furthermore gene-gene and gene-environment studies will be feasible.