Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index

Abstract

Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO), some of which have been previously associated with obesity and type 2 diabetes (T2D). We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE) Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip. A meta-analysis of the two study populations replicated the well-described associations between FTO variants and obesity (odds ratio [OR] = 1.25, 95% Confidence Interval = 1.11–1.24, p = 2.10 × 10−9) and FTO variants and T2D (OR = 1.14, 95% CI = 1.08–1.21, p = 2.34 × 10−6). The meta-analysis also demonstrated that FTO variant rs8050136 was significantly associated with sleep apnea (OR = 1.14, 95% CI = 1.07–1.22, p = 3.33 × 10−5); however, the association was attenuated after adjustment for body mass index (BMI). Novel phenotype associations with obesity-associated FTO variants included fibrocystic breast disease (rs9941349, OR = 0.81, 95% CI = 0.74–0.91, p = 5.41 × 10−5) and trends toward associations with non-alcoholic liver disease and gram-positive bacterial infections. FTO variants not associated with obesity demonstrated other potential disease associations including non-inflammatory disorders of the cervix and chronic periodontitis. These results suggest that genetic variants in FTO may have pleiotropic associations, some of which are not mediated by obesity.

Distinct Penetrance of Obesity-Associated Susceptibility Alleles in the Hungarian General and Roma Populations

“…However, despite intensive research its exact pathomechanism is still not completely understood [40]. The impacts of FTO gene polymorphisms found in this study were consistent with previous reports not only in European-descent populations [28,35,36] but also in the Slovakian Roma [41], indicating that the effect of these susceptibility loci for obesity persists across populations with various ancestral origins. Nonetheless, common variants in the FTO gene did not show an obvious association with obesity-related phenotypes in Spanish Roma populations [42].…”

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

“…We also examined generalizability of previously reported AHI candidate gene results to our Hispanic/Latino cohorts (see Table E6) (23)(24)(25)(26)(27)(28)(29)(30)(31). Of 17 SNPs tested We searched for SNPs with supporting ENCODE or Roadmap Epigenomics regulatory evidence as calculated by HaploReg (33).…”

Genetic Determinants of Sleep Apnea Syndrome: A Review of Contemporary Data

“…Была обнару-жена достоверная связь генетического варианта rs8050136 гена FTO -связанного с жировой массой и ожирением -и синдрома ночного апноэ (отноше-ние рисков 1,14 при p=0,0000023). Обнаружены и дру-гие взаимосвязи этого генетического варианта, в том числе, не связанные напрямую с ожирением [2].…”