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Background  Independent genome-wide association studies (GWAS) showed an obesogenic effect of two single nucleotide polymorphisms (SNP; rs12970134 and rs17782313) more than 150 kb downstream of the melanocortin 4 receptor gene ( MC4R ). It is unclear if the SNPs directly influence MC4R function or expression, or if the SNPs are on a haplotype that predisposes to obesity or includes functionally relevant genetic variation (synthetic association). As both exist, functionally relevant mutations and polymorphisms in the  MC4R  coding region and a robust association downstream of the gene,  MC4R  is an ideal model to explore synthetic association.    Methodology/Principal Findings  We analyzed a genomic region (364.9 kb) encompassing the  MC4R  in GWAS data of 424 obesity trios (extremely obese child/adolescent and both parents). SNP rs12970134 showed the lowest p-value (p = 0.004; relative risk for the obesity effect allele: 1.37); conditional analyses on this SNP revealed that 7 of 78 analyzed SNPs provided independent signals (p≤0.05). These 8 SNPs were used to derive two-marker haplotypes. The three best (according to p-value) haplotype combinations were chosen for confirmation in 363 independent obesity trios. The confirmed obesity effect haplotype includes SNPs 3′ and 5′ of the  MC4R.  Including  MC4R  coding variants in a joint model had almost no impact on the effect size estimators expected under synthetic association.    Conclusions/Significance  A haplotype reaching from a region 5′ of the  MC4R  to a region at least 150 kb from the 3′ end of the gene showed a stronger association to obesity than single SNPs. Synthetic association analyses revealed that  MC4R  coding variants had almost no impact on the association signal. Carriers of the haplotype should be enriched for relevant mutations outside the  MC4R  coding region and could thus be used for re-sequencing approaches. Our data also underscore the problems underlying the identification of relevant mutations depicted by GWAS derived SNPs.

Investigation of a Genome Wide Association Signal for Obesity: Synthetic Association and Haplotype Analyses at the Melanocortin 4 Receptor Gene Locus