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.

Keywords: BMI; Exome chip; FTO; PheWAS; genetic association; pleiotropy.

Figure 1

PheWAS plots for FTO rs8050136 with and without BMI adjustment. The pink horizontal line represents p = 4.95 × 10⁻⁵, which is the Bonferroni correction, and the blue horizontal line represents an FDR q = 0.05 (p = 2.48 × 10⁻⁴). (A) without BMI adjustment, (B) with BMI adjustment, and (C) most significant phenotypic associations before and after BMI adjustment (BMI-unadjusted values are shown as triangles and average BMI values are shown as dots) plotted on the same axis. The colors of points indicate the membership according to the phenotype classes identified on the X axis.

Figure 2

PheWAS plots for other obesity associated SNPs in high LD with rs8050136. These plots show unadjusted values and the average BMI adjusted values on the same axis. These SNPs are associated with BMI and have different correlations with rs8050136. These SNPs are present in both datasets and are presented as meta-analyses below. The pink horizontal line represents p = 4.95 × 10⁻⁵, which is the Bonferroni correction, and the blue horizontal line represents an FDR q = 0.05 (p = 2.48 × 10⁻⁴). (A) rs9939609 is reported widely in the literature and has a nearly identical pattern of associations to rs8050136 (r² = 0.96). (B) rs9941349 also has a similar pattern to rs8050136 but cystic mastopathy is marginally more associated (p = 5.41 × 10⁻⁵, OR = 0.81 before BMI adjustment) than in rs8050136 (r² = 0.88).

Figure 3

PheWAS plots for other obesity associated SNPs in low LD with rs8050136. These plots show values without adjustment for BMI (shown as triangles) and with adjustment for average BMI (shown as dots) plotted on the same axis. (A) rs6499640 is in both datasets with a lower LD with rs8050136 (r² = 0.06) and has a different phenotype pattern than rs8050136 (B) rs16952520 is only present in the eMERGE population and has low LD with rs8050136 (r² = 0.03) and while not strongly associated with obesity or diabetes does show significant association with non-inflammatory disorders of the cervix (OR = 6.76, p = 1.92 × 10⁻⁶), unaffected by adjustment for BMI (OR = 6.66, p = 2.36 × 10⁻⁶) (C) rs7199182 is only present in the eMERGE population and has a low LD with rs8050136 (r² = 0.04) and is associated with chronic periodontitis before and after BMI adjustment (no adjustment: p = 5.40 × 10⁻⁵; BMI adjustment: p = 5.20 × 10⁻⁵).