Abstract
Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P≤0.05) depending on parental origin—among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P≤0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings.
Highlights
Genome-Wide Association Studies (GWAS) were extremely successful in identifying novel and unexpected loci playing a role in common obesity [1]
Recent work suggests that noncoding variants in intron 1 of fat mass and obesity associated (FTO) may disrupt an enhancer of IRX3 which influences the expression of IRX3 [20,21]
Despite the reported relatively large genetic effect size of FTOvariants [12] and the general success of GWAS, large proportions of the variability in BMI cannot be explained by SNP allele variability [35]
Summary
Genome-Wide Association Studies (GWAS) were extremely successful in identifying novel and unexpected loci playing a role in common obesity [1]. Often [7] the same variants had an impact on both BMI variation in the general population and on highly selected phenotypes such as extreme obesity with an early onset (Hinney et al [8], Scherag et al [9], Meyre et al [10]). This is true for the FTO gene which was discovered in 2007. The mechanisms of noncoding variants in intron 3 remain unclear so far
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