ABSTRACT

Obesity is major health problem in many developing countries. In the United States, approximately 17% of children and adolescents are overweight and one-third of adults are estimated to be obese (1). Body mass index (BMI) is thought to have a substantial genetic component with heritability estimates of 40 to 70% (2). However, genetic variants related to obesity have proved difficult to find and replicate. With the advent of genome-wide scans, new efforts to comprehensively search the genome have begun to identify common variants associated with susceptibility to obesity, such as the recently discovered common SNP in FTO (3). As part of the Genomic Investigation of Anthropometric Traits (GIANT) consortium, we have pooled the results from genome-wide scans in three cohorts to identify genetic variants associated with BMI in early adulthood (N~5,500). We have identified over 80 promising loci associated with BMI at age 20 with a p-value of 10-5 or smaller and are currently replicating 45 of the top SNPs in an additional 10,000 subjects from other cohorts. We propose to follow-up the loci that are replicated in the ALSPAC cohort to determine if the SNPs are also associated with BMI in childhood.

BACKGROUND

Although inherited factors are thought to contribute to obesity, results from candidate gene and genetic linkage studies of obesity have been largely inconsistent [reviewed in (4,5)]. However, recently, as the result of large genome-wide association studies, common variants in the FTO gene were found to be associated with susceptibility to obesity (3) and obesity-related traits (6). The finding of FTO has spurred renewed interested in discovering additional loci associated with obesity and obesity-related traits and spawned large collaborative efforts, such as the Genomic Investigation of Anthropometric Traits (GIANT) consortium, which is an effort to pool genome-wide scan results from multiple cohorts and identify loci associated with height and obesity.

PRELIMINARY DATA

As part of the GIANT consortium, we have pooled the results from three genome-wide scans (encompassing 2.5 million single nucleotide polymorphisms that were either directly genotyped or imputed) with information on BMI at age 18 or 20 to identify genetic variants associated with BMI in early adulthood (N~5,500). We have identified approximately 87 independent loci with a p-value of 10-5 or smaller for BMI in early adulthood. Some of these loci are located near or in potentially promising genes, and we are currently genotyping 45 of the top loci in an additional 10,000 subjects from other cohorts with information on BMI in early adulthood.

PROPOSED PROJECT

Assuming that some of the loci identified in our initial meta-analysis are replicated in the follow-up cohorts, we propose to genotype those same SNPs in the ALSPAC cohort to determine whether the loci are also associated with BMI in childhood. We estimate that only a few loci will be convincingly replicated in our follow-up cohorts; however, it is conceivable that up to 10 SNPs may warrant further study. We plan to genotype these SNPs in the same children (N~7,500) that were genotyped in the recently submitted manuscript by Loos et al. (7). Similar to the study by Loos et al., we plan to evaluate the association with BMI at ages 7-11 as well as fat and lean body mass as measured by whole-body dual energy X-ray absorptiometry (DEXA) scan at age 9.

DATA REQUESTED

Biological Samples: DNA (~10 ng of DNA per genotype) for children. We plan to genotype up to 10 SNPs depending on the results of our replication study.

Clinical measurements: Height, weight, and BMI at ages 7-11 years for children. Fat, lean body, and bone mass as measured by a whole-body dual energy X-ray absorptiometry (DEXA) scan in children at age 9.