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

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 diag...

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Autores principales: Tcheandjieu, Catherine, Aguirre, Matthew, Gustafsson, Stefan, Saha, Priyanka, Potiny, Praneetha, Haendel, Melissa, Ingelsson, Erik, Rivas, Manuel A., Priest, James R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735621/
https://www.ncbi.nlm.nih.gov/pubmed/33226994
http://dx.doi.org/10.1371/journal.pgen.1008802
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author Tcheandjieu, Catherine
Aguirre, Matthew
Gustafsson, Stefan
Saha, Priyanka
Potiny, Praneetha
Haendel, Melissa
Ingelsson, Erik
Rivas, Manuel A.
Priest, James R.
author_facet Tcheandjieu, Catherine
Aguirre, Matthew
Gustafsson, Stefan
Saha, Priyanka
Potiny, Praneetha
Haendel, Melissa
Ingelsson, Erik
Rivas, Manuel A.
Priest, James R.
author_sort Tcheandjieu, Catherine
collection PubMed
description 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.
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spelling pubmed-77356212020-12-22 A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population Tcheandjieu, Catherine Aguirre, Matthew Gustafsson, Stefan Saha, Priyanka Potiny, Praneetha Haendel, Melissa Ingelsson, Erik Rivas, Manuel A. Priest, James R. PLoS Genet Research Article 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. Public Library of Science 2020-11-23 /pmc/articles/PMC7735621/ /pubmed/33226994 http://dx.doi.org/10.1371/journal.pgen.1008802 Text en © 2020 Tcheandjieu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tcheandjieu, Catherine
Aguirre, Matthew
Gustafsson, Stefan
Saha, Priyanka
Potiny, Praneetha
Haendel, Melissa
Ingelsson, Erik
Rivas, Manuel A.
Priest, James R.
A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population
title A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population
title_full A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population
title_fullStr A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population
title_full_unstemmed A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population
title_short A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population
title_sort phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735621/
https://www.ncbi.nlm.nih.gov/pubmed/33226994
http://dx.doi.org/10.1371/journal.pgen.1008802
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