The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts

A SNP upstream of the INSIG2 gene, rs7566605, was recently found to
be associated with obesity as measured by body mass index (BMI) by
Herbert and colleagues. The association between increased BMI and
homozygosity for the minor allele was first observed in data from a
genome-wide association scan of 86,604 SNPs in 923 related
individuals from the Framingham Heart Study offspring cohort. The
association was reproduced in four additional cohorts, but was not
seen in a fifth cohort. To further assess the general
reproducibility of this association, we genotyped rs7566605 in nine
large cohorts from eight populations across multiple ethnicities
(total n = 16,969). We tested this variant for association with BMI
in each sample under a recessive model using family-based,
population-based, and case-control designs. We observed a
significant (p < 0.05) association in five cohorts but saw no
association in three other cohorts. There was variability in the
strength of association evidence across examination cycles in
longitudinal data from unrelated individuals in the Framingham
Heart Study Offspring cohort. A combined analysis revealed
significant independent validation of this association in both
unrelated (p = 0.046) and family-based (p = 0.004) samples. The
estimated risk conferred by this allele is small, and could easily
be masked by small sample size, population stratification, or other
confounders. These validation studies suggest that the original
association is less likely to be spurious, but the failure to
observe an association in every data set suggests that the effect
of SNP rs7566605 on BMI may be heterogeneous across population
samples.