A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population

Abstract

The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

Fig 1

Primary PheWAS results: Variant level findings are displayed in panel (a) The red line represents the level of significance after Bonferroni correction (p<2.7x10^-07). The color indicates variant in each gene and the shape indicates each phenotype (ex: variants in PTPN11 are represented in blue, and the association with diastolic blood pressure indicated with the sign +). Correlation plot of association between phenotypes and the subset of independent variants within each gene is displayed in panel (b). The points represent the z-score and the color represent the direction of the association. The color varies from purple (inverse association) to red (positive association). The size of the point corresponds to the p-value (-log10(p)); the stars indicate variants associated with multiple phenotypes.

Fig 2. Primary PheWAS results at a gene level.

Plot of PheWAS results for all genes and phenotypes (a). The red line represents the level of significance after FDR correction. Genes are represented by color and phenotypes are indicated by shape. Correlation plot for the set of significant gene–phenotype pairs. (b). The color represents the p-value of association and varies from none associated (grey-white) to significant association (red-dark red).

Fig 3. PheWAS result and linkage plot for variants with pleiotropy in FBN1.

Associations between variants associate with multiple phenotypes (a) and linkage between the variants in FBN1 (b). The red line represents the level of significance after Bonferroni correction (p = 2.7x10^-07).

Fig 4. PheWAS result and linkage plot for variants with pleiotropy in RAS-opathy genes.

Associations between variants with pleiotropic effects in MAP2K1, PTPN11, SOS2 and RASA2, and HPO terms (a) and linkage between the variants (b). The red line represents the level of significance after Bonferroni correction (p = 2.7x10^-07).