title: A multilevel linear mixed model of the association between candidate genes and weight and body mass index using the Framingham longitudinal family data.
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).
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.affiliation: Center for Neurobehavioral Genetics, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, 695 South Charles E Young Drive, Los Angeles, California 90095, USA.
authors.forename: Berit
authors.initials: B
authors.lastname: Kerner
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Zhao
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Ruth Jf
authors.initials: RJ
authors.lastname: Loos
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sharp
authors.affiliation: Department of Education, 2005 East Moore Hall, University of California at Los Angeles, California 90095, USA.
authors.forename: Bengt O
authors.initials: BO
authors.lastname: Muthén
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham