Abstract
Obesity has become an epidemic in many countries and is one of the major risk conditions for disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension. Recent genome-wide association studies have identified two genes (FTO and near MC4R) that were unequivocally associated with body mass index (BMI) and obesity. For the Genetic Analysis Workshop 16, data from the Framingham Heart Study were made available, including longitudinal anthropometric and metabolic traits for 7130 Caucasian individuals over three generations, each with follow-up data at up to four time points. We explored the associations between four single-nucleotide polymorphisms (SNPs) on FTO (rs1121980, rs9939609) or near MC4R (rs17782313, rs17700633) with weight and BMI under an additive model. We applied multilevel linear mixed model for continuous outcomes, using the Affymetrix 500k genome-wide genotype data for the four SNPs. The results of the multilevel modeling in the entire sample indicated that the minor alleles of the four SNPs were associated with higher weight and higher BMI. The most significant associations were between rs9939609 and weight (p = 4.7 x 10-6) and BMI (p = 8.9 x 10-8). The results also showed that, for SNPs at FTO, the homozygotes for the minor allele had the most pronounced increase in weight and BMI, while the common allele homozygotes gained less weight and BMI during the follow-up period. Linkage disequilibrium (LD) between the two FTO SNPs was strong (D' = 0.997, r2 = 0.875) but their haplotype was not significantly associated with either weight or BMI. The two SNPs near MC4R were in weak LD (D' = 0.487, r2 = 0.166).
Highlights
As a major contributor to chronic disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension, obesity has reached epidemic levels in both developed countries and developing countries
We will analyze the longitudinal family data of the Framingham Heart Study [5] provided for Genetic Analysis Workshop 16, by evaluating associations between weight, body mass index (BMI), and single-nucleotide polymorphisms (SNPs) on FTO or near MC4R, which were recently identified to be consistently associated with obesityrelated measures through cross-sectional genome-wide association studies [1,4]
With the exception of only one SNP on BMI, our linear mixed models confirmed that the minor alleles of the SNPs rs1121980, rs9939609, and rs17782313 were significantly associated with higher weight and BMI
Summary
As a major contributor to chronic disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension, obesity has reached epidemic levels in both developed countries and developing countries. It is a multi-factorial disorder that is attributable to multiple genetic and environmental factors. We will analyze the longitudinal family data of the Framingham Heart Study [5] provided for Genetic Analysis Workshop 16, by evaluating associations between weight, BMI, and single-nucleotide polymorphisms (SNPs) on FTO (rs1121980, rs9939609) or near MC4R (rs17782313, rs17700633), which were recently identified to be consistently associated with obesityrelated measures through cross-sectional genome-wide association studies [1,4]
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