Abstract 15067: Novel Non-Synonymous Exonic Variants in PCDHA10 are Associated with Obesity
Background: More than 1/3 of American adults and 1/6 of American children are obese. Obesity is associated with many morbid conditions such as heart disease, stroke and diabetes and has been shown to be influenced by genetic factors. Although several genes associated with obesity have been identified, much variance remains to be explained.
Methods: Using data from the Family Heart Study (FamHS; N=896) we divided subjects into those with BMI ≥ 35 kg/m2 (extreme obesity cases), those with BMI ≥ 30 kg/m2 (obese cases), and those with 18.5 ≤ BMI ≤ 27 kg/m2 (normal weight controls). GWAS analysis was performed to identify significant SNPs associated with extreme obesity. Pooled exomic sequencing of the peak associated region and the exons within the block of linkage disequilibrium (LD) was performed to identify non-synonymous variants. Individual genotyping of significant variants was performed to allow more powerful statistical tests of association.
Results: GWAS analysis identified 7 SNPs significantly (p < 5.0 E-08) associated with extreme obesity. All 7 variants localized to a region on 5q31 within a block of strong LD with overlapping exons encoding a family of proteins known as protocadherins (PCDHs). Pooled exomic sequencing of this region identified two non-synonymous variants that were associated with obesity. Individual genotyping confirmed that one of these variants (rs630162) was significantly associated with extreme obesity (p = 0.024) in addition to the most significant GWAS hit (rs3822343; p = 5.2e-07) and was in significant LD (D’=0.968) with the GWAS hit. The other variant (rs251362) was nominally associated with extreme obesity (p= 0.053) and was in moderate LD with the GWAS hit (D’=636). Both exonic variants, and the GWAS hit, were significantly associated with quantitative BMI (0.0001 ≤ p ≤ 0.025), suggesting that the coding variants also influence adiposity.
Conclusions: We identified novel non-synonymous exonic variants associated with obesity located within the PCDH gene cluster, a region that has not been previously implicated in obesity. PCDHs have been shown to act as signaling or receptor molecules; it is interesting to speculate that these variants produce protein changes that affect adiposity through these mechanisms.
- © 2012 by American Heart Association, Inc.