Common variants near MC4R are associated with fat mass, weight and risk of obesity

Abstract

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.

Figure 1

Regional plot of chromosome 18q21 (55,700–56,400 kb), showing the association signals for obesity for the meta-analysis of all 16,876 samples with genome-wide association scans. On the x axis is chromosomal position in kilobases (as NCBI build 35 coordinates), and on the y axis is the P value for association (expressed as −log₁₀ P value). The imputed data signals are shown in gray diamonds and the directly genotyped signals in white. Estimated recombination rates (taken from HapMap) are plotted (light blue) to reflect the local LD structure around the associated SNP. Gene annotations were taken from the University of California Santa Cruz genome browser. The yellow diamond corresponds to the directly genotyped SNP in this region, which shows the strongest association with obesity (rs17782313, P = 2.9 × 10⁻⁶), the lower blue diamond represents the result from rs17700633 (P = 4.8 × 10⁻⁵, directly genotyped), and the green diamond represents the result from rs2229616 (or V103I, P = 0.056, imputed). LD structure across the interval, as calculated by D′, and r² measures are shown in Supplementary Figure 5a.

Figure 2

Meta-analysis plot showing the rs17782313[C] per-allele effect size on BMI in 77,228 adults, expressed in log₁₀BMI sex-specific Z-score units.

Figure 3

Effects of rs17782313 on regulation of weight in early life. (a) Longitudinal data for BMI at age 7–11 for children in the ALSPAC study by rs17782313 genotypes. Mean values represented as geometric means and back-transformed 95% confidence intervals. P values represent significance of the additive model (per-allele effect) of log₁₀-transformed data, adjusted for sex. (b) Association between rs17782313 and body fat percentage in 9-year-old children from the ALSPAC study. Mean values represented as geometric means and back-transformed 95% confidence intervals. P values represent significance of the additive model (per-allele effect) of log₁₀-transformed data, adjusted for sex. (c) Meta-analysis plot showing the rs17782313[C] per-allele effect size on risk of severe obesity in childhood and adolescence in 10,583 children from three studies.

Figure 4

Association between the combined rs17782313 and FTO genotypes and BMI in adults (EPIC-Norfolk, n = 15,622) and children (ALSPAC age 7 years, n = 5,779). BMI is expressed in log₁₀BMI Z-score units adjusted for age (in adults) and sex. Both SNPs have a significant additive effect on BMI in adults (rs17782313, P = 4.0 × 10⁻⁴; rs1121980, P = 2.0 × 10⁻¹⁴) and in children (rs17782313, P = 8.0 × 10⁻⁶; rs9939609, P = 7.6 × 10⁻⁵).