Loos RJ, Lindgren CM, Li S, et al.. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 40: 768-775

MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Nature Genetics (Impact Factor: 29.35). 07/2008; 40(6):768-75. DOI: 10.1038/ng.140
Source: PubMed


To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

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    • "Various susceptibility genes for type 2 diabetes have recently been identified for several populations through genome-wide association studies (Ridderstråle and Groop, 2009). Genetic variants in FTO, MC4R, SLC30A8, and KCNQ1 were first reported by several studies performed in European and Asian populations (Saxena et al., 2007; Scott et al., 2007; Sladek et al., 2007; Zeggini et al., 2007; Loos et al., 2008; Yasuda et al., 2008). These polymorphisms have been confirmed in multiple studies examining various populations (Horikoshi et al., 2007; Steinthorsdottir et al., 2007; Omori et al., 2008). "
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    ABSTRACT: Recent genome wide association studies identified many loci in several genes that have been consistently associated with type 2 diabetes mellitus in various ethnic populations. Among the genes that were most strongly associated with diabetes were fat mass- and obesity-associated, melanocortin 4 receptor, solute carrier family 30 member 8 (SLC30A8), and a member of the potassium voltage-gated channels. In the present study, we examined the association between variants in fat mass- and obesity-associated [rs9939609 (A/T)], melanocortin 4 receptor [rs17782313 (C/T), and rs12970134 (A/G)], SLC30A8 [rs13266634 (C/T)], and a member of the potassium voltage-gated channels [rs2237892(C/T)] genes in diabetes patients from Saudi Arabia. Genotypes were determined using the TaqMan single-nucleotide polymorphism genotype analysis technique. Minor allele frequency of the 4 variants tested was comparable between type 2 diabetes cases and controls. We observed an association between allele variants of SLC30A8 [rs13266634 (C/T)] and type 2-diabetes (P = 0.04). The other single-nucleotide polymorphisms examined in this study showed moderate or no correlation with diabetes in Saudis. Our data indicate that the SLC30A8 polymorphisms are associated with type 2 diabetes in the Saudi population. There is no evidence supporting an association between variants in the fat mass- and obesity-associated and melanocortin 4 receptor, and a member of the potassium voltage-gated channels genes and type 2 diabetes in the Saudi population.
    Genetics and molecular research: GMR 12/2014; 13(4):10194 - 10203. DOI:10.4238/2014.December.4.14 · 0.78 Impact Factor
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    • "To this end, the use of high throughput arrays has facilitated the genotyping of thousands of common variants covering more than 75 % of the genome in large population-based cohorts on whom body mass index data is available. The first GWAS-derived loci detected were intronic variants in the FTO (fat mass and obesity-associated) gene (Frayling et al. 2007; Dina et al. 2007) and variants approximately 200 kb downstream of MC4R (Loos et al. 2008). To date, more than 50 genetic loci relevant for body weight regulation have been identified by GWAS approaches (Loos 2012). "
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    • "These findings will be informative about which genetic determinants of BMI are consistent across populations, and which differ. It is compelling that our investigations show that many of the loci previously indicated as being associated with BMI [15], [17]–[20], [41], [42] contain no SNVs that are strongly associated with BMI in our sample. While the participants of these studies were primarily of recent European descent, one study in an African American population [21] and one in a Japanese population [22] found an association signal from a variant in the vicinity of FTO, which replicated a signal seen in populations of European ancestry [15], [18], [19], [41], [42]. "
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    ABSTRACT: Many health outcomes are influenced by a person's body mass index, as well as by the trajectory of body mass index through a lifetime. Although previous research has established that body mass index related traits are influenced by genetics, the relationship between these traits and genetics has not been well characterized in people of South Asian ancestry. To begin to characterize this relationship, we analyzed the association between common genetic variation and five phenotypes related to body mass index in a population-based sample of 5,354 Bangladeshi adults. We discovered a significant association between SNV rs347313 (intron of NOS1AP) and change in body mass index in women over two years. In a linear mixed-model, the G allele was associated with an increase of 0.25 kg/m2 in body mass index over two years (p-value of 2.3·10-8). We also estimated the heritability of these phenotypes from our genotype data. We found significant estimates of heritability for all of the body mass index-related phenotypes. Our study evaluated the genetic determinants of body mass index related phenotypes for the first time in South Asians. The results suggest that these phenotypes are heritable and some of this heritability is driven by variation that differs from those previously reported. We also provide evidence that the genetic etiology of body mass index related traits may differ by ancestry, sex, and environment, and consequently that these factors should be considered when assessing the genetic determinants of the risk of body mass index-related disease.
    PLoS ONE 08/2014; 9(8):e105062. DOI:10.1371/journal.pone.0105062 · 3.23 Impact Factor
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