In the current study, we performed a GWAS on obesity and obesity-related traits. The FTO
gene reached genome-wide significance in this cohort with an odds ratio of 1.6. The MC4R
gene is the second gene found by GWAS to be associated with BMI 
, and, while only marginally associated with obesity in our study, its odds ratio was 1.3. Given our modest sample size in GWAS, we estimate that the power to detect association (with perfect SNP tagging) at P<5×10−8
is 78.8% and 0.18% for FTO
, respectively. These odds ratio estimates in our data are higher than previous reports, for example, odds ratio for FTO
is 1.3 in a study for early-onset obesity 
, for FTO
are 1.46 and 1.02 in a study for extreme obesity 
, or 1.25 and 1.26 in a study on morbidly obese adults with familial obesity 
, or 1.27 and 1.12 for obesity 
. We note that the Hinney et al report investigated early onset extreme obesity and reported an odds ratio of 1.67 for FTO 
, comparable to our study. Therefore, the increased effect size could be due to the specific sample ascertainment scheme that we have used, that is, we sampled from the extreme tails of a quantitative trait distribution based on BMI. Even with the augmented sample of cases, family members and controls, no other SNPs reached genome wide significance. The results therefore strongly suggest that FTO
might be the only two major-effect genes for obesity with common variants in populations of European ancestry. Our study also represents an example where enrichment of extreme cases and controls can lead to increased odds ratio, and subsequently leads to improved power to detect associations.
The association between waist to hip ratio and the NRXN3
gene is of interest, as this is the third time the gene has been associated with body fat distribution 
. Neurexins are expressed in nervous tissue and are thought to be involved in cell adhesion during synapse formation 
. Besides fat distribution, NRXN3
has been associated with several other traits, including addictions and schizophrenia 
. Identifying the specific causal variant may be difficult because NRXN3
is an extremely large gene (~1.5 Mb) 
. It is controlled by two promoters and has multiple transcripts. The SNPs associated with weight and fat distribution lie in different parts of the gene and will likely involve different transcripts with potentially different functions. The associated SNP in our study, rs11624704, appears to be about 85 kb upstream of the first exon, while those for the previous two studies, rs10150332 and rs10146997, appear to be about 8 kb apart near exon 11.
In conclusion, we have assayed a sample collection of obese cases, families and never-overweight controls, and performed association analysis on obesity and multiple quantitative phenotype measures. We obtained strong support for FTO as well as suggestive confirmation of several previously identified BMI-associated genes in obesity. Another outcome of our study is the identification of new candidate genes for obesity-related traits. Of particular interest is the association of NRXN3 with body fat distribution among extremely obese individuals.