Identification of human obesity genes with focus on developmental aspects

Coordinator:    Prof. Dr. Anke Hinney
Institution: University of Duisburg-Essen, Department of Child and Adolescent Psychiatry
The aim of the subproject was the identification of genetic variants predisposing to obesity in children and adolescents as well as in adults. Identification of genes was mainly performed by genome-wide association studies (GWAS). About 40 genes and genetic loci with relevance for body weight regulation are known to date. Each variant only has a small effect on body weight (Figure 1)

Figure 1: Effect values for genetic loci that influence body weight which were identified in meta-analyses of genome-wide association studies (GWAS). The abbreviation of the gene name represents the identified region tagged by a SNP. The percentages above the columns show the risk allele frequency. X axis: Loci identified in European study groups are grey: Speliotes et al., Nat Genet. 2010; loci identified in Asian study groups are white: Wen et al. Nat Genet. 2012, Okada et al. Nat Genet. 2012; loci identified in extreme early onset obesity are black: Scherag et al. PLoS Genet. 2010, Bradfield et al. Nat Genet. 2012.

By contrast, there are infrequent mutations which can have large implications for the phenotype. The group in Essen showed that individuals with functionally relevant mutations in the MC4R gene are on average 15 (men) to 30 (women) kgs heavier (Dempfle et al., J Med Genet. 2004). The MC4R gene encodes a receptor located in the hypothalamus which plays a central role in the regulation of energy homeostasis (Figure 2).

Figure 2: Energy homeostasis signalling in the hypothalamus (adapted from Barsh & Schwartz, Nature 2002). Ghrelin is secreted from the stomach and activates the ghrelin receptor (GHSR) on the AGRP/NPY neurons. Fat tissue secretes leptin which reduces the signaling activity of the AGRP/NPY neurons (orange) as an antagonist of ghrelin. Additionally, leptin activates POMC/Cart neurons (yellow) by binding to the leptin receptor (LEPR). The AGRP/NPY neurons and the POMC/Cart neurons reciprocally regulate each other via the receptors for melanocortin 3 (MC3R) and neuropeptide Y (Y1R). Both AGRP/NPY neurons and POMC/Cart neurons also activate the melanocortin 4 receptors in secondary order neurons (red). In turn, these secondary order neurons regulate food intake and influence the body weight by satiety.

Our group performed the first GWAS for early onset obesity. By array-based technologies 500,000 gene variants had been analyzed in 487 extremely obese children and adolescents and 442 healthy lean controls (Hinney et al. 2007). The “fat mass and obesity associated” gene had been identified, which had been confirmed in many independent studies. It is currently the best investigated obesity polygene. Moreover, the world-wide first family-based GWAS for obesity was performed. A total of 1 Mio gene variants had been analyzed in 705 extremely obese children and both parents. As the identified gene variants only have small effects on body weight, confirmation of the findings in (especially large) independent samples is important. Therefore, data of the obesity network (SP1 and WB2 with TP15) were integrated in different large international consortia:

(a)    In the GIANT (Genetic Investigation of Anthropometric Traits) consortium gene variants of about 250.000 individuals were analysed (app. 35.000 individuals from the obesity network). This study identified 32 genetic loci (18 previously unknown) with effect on body weight regulation. Each variant – individually or in combination – has an effect on body weight increase of about 130 grams to 1.5 kgs (Speliotes et al., Nat Genet. 2010). Considering only the extremes of the weight distribution, i.e. the 5 % individuals with the highest and lowest BMI (“body mass index”), seven additional loci with obesity association could be identified (Berndt et al., Nat Genet. 2013).

(b)    Moreover, in the EGG (Early Growth Genetics) consortium, two new genetic loci for early-onset obesity were identified together with colleagues from different countries. Data of 5,530 extremely obese children and adolescents (BMI ? 95th age and sex specific percentile, of these 705 family trios from this NGFN-Plus network) was compared to data of 8,318 normal weight controls (BMI < 50th age and sex specific percentile) of European heritage (Bradfield et al., Nat Genet. 2012).
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