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

Autoři: Catherine Tcheandjieu aff001;  Matthew Aguirre aff002;  Stefan Gustafsson aff001;  Priyanka Saha aff001;  Praneetha Potiny aff001;  Melissa Haendel aff005;  Erik Ingelsson aff001;  Manuel A. Rivas aff004;  James R. Priest aff001
Působiště autorů: Stanford Cardiovascular Institute, Stanford University, Stanford, Stanford, California, United States of America aff001;  Department of Pediatric Cardiology Stanford University School of Medicine, Stanford, California, United States of America aff002;  Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America aff003;  Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California, United States of America aff004;  Department of Medical Informatics and Clinical Epidemiology, School of Medicine, Oregon Health & Science University (OHSU), Oregon, United States of America aff005;  Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America aff006;  Stanford Diabetes Research Center, Stanford University, Stanford, California, United States of America aff007;  Chan-Zuckerberg Biohub, San Francisco, California, United States of America aff008
Vyšlo v časopise: A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population. PLoS Genet 16(11): e1008802. doi:10.1371/journal.pgen.1008802
Kategorie: Research Article
doi: https://doi.org/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.

Klíčová slova:

Adipose tissue – Alleles – Blood pressure – Body Mass Index – Genetics of disease – Hypothyroidism – Marfan syndrome – Phenotypes


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