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

• Published in: PLoS genetics Vol. 16; no. 11; p. e1008802
• Main Authors: Tcheandjieu, Catherine, Aguirre, Matthew, Gustafsson, Stefan, Saha, Priyanka, Potiny, Praneetha, Haendel, Melissa, Ingelsson, Erik, Rivas, Manuel A, Priest, James R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-11-2020; Public Library of Science (PLoS)
• Subjects: Adipose tissue; Alagille syndrome; Alagille Syndrome - genetics; Alleles; Bilirubin; Biobanks; Biological Variation, Population - genetics; Biology and Life Sciences; Birth weight; Blood pressure; Body fat; Body height; Body mass index; Connective tissue diseases; Creatinine; DiGeorge syndrome; DiGeorge Syndrome - genetics; Disease; Epigenetic inheritance; Extracellular matrix; Female; Gene Frequency - genetics; Genes; Genetic aspects; Genetic Association Studies - methods; Genetic Predisposition to Disease - genetics; Genetic research; Genetic Testing - methods; Genetic Variation - genetics; Genome-Wide Association Study - methods; Genomes; Genotype & phenotype; Health aspects; Humans; Hypercholesterolemia; Hyperlipidemia; Hypothyroidism; Male; Marfan syndrome; Marfan Syndrome - genetics; Marfan's syndrome; Matrix protein; Medicine and Health Sciences; Mutation; Noonan syndrome; Noonan Syndrome - genetics; Ontology; Phenotype; Phenotypes; Polymorphism, Single Nucleotide - genetics; Population; Small for gestational age; United Kingdom; Whites - genetics; United Kingdom; United States; United Kingdom > UK
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008802

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.