PheWAS and cross-disorder analysis reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders.
GWAS
PRS
PheWAS
autoimmune disorders
cross-disorder
meta-analysis
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
18
01
2023
accepted:
04
09
2023
medline:
1
11
2023
pubmed:
9
10
2023
entrez:
9
10
2023
Statut:
epublish
Résumé
Autoimmune disorders (ADs) are a group of about 80 disorders that occur when self-attacking autoantibodies are produced due to failure in the self-tolerance mechanisms. ADs are polygenic disorders and associations with genes both in the human leukocyte antigen (HLA) region and outside of it have been described. Previous studies have shown that they are highly comorbid with shared genetic risk factors, while epidemiological studies revealed associations between various lifestyle and health-related phenotypes and ADs. Here, for the first time, we performed a comparative polygenic risk score (PRS) - Phenome Wide Association Study (PheWAS) for 11 different ADs (Juvenile Idiopathic Arthritis, Primary Sclerosing Cholangitis, Celiac Disease, Multiple Sclerosis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Type 1 Diabetes, Systemic Lupus Erythematosus, Vitiligo Late Onset, Vitiligo Early Onset) and 3,254 phenotypes available in the UK Biobank that include a wide range of socio-demographic, lifestyle and health-related outcomes. Additionally, we investigated the genetic relationships of the studied ADs, calculating their genetic correlation and conducting cross-disorder GWAS meta-analyses for the observed AD clusters. In total, we identified 508 phenotypes significantly associated with at least one AD PRS. 272 phenotypes were significantly associated after excluding variants in the HLA region from the PRS estimation. Through genetic correlation and genetic factor analyses, we identified four genetic factors that run across studied ADs. Cross-trait meta-analyses within each factor revealed pleiotropic genome-wide significant loci. Overall, our study confirms the association of different factors with genetic susceptibility for ADs and reveals novel observations that need to be further explored.
Identifiants
pubmed: 37809097
doi: 10.3389/fimmu.2023.1147573
pmc: PMC10552152
doi:
Substances chimiques
HLA Antigens
0
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1147573Informations de copyright
Copyright © 2023 Topaloudi, Jain, Martinez, Bryant, Reynolds, Zagoriti, Lagoumintzis, Zamba-Papanicolaou, Tzartos, Poulas, Kleopa, Tzartos, Georgitsi, Drineas and Paschou.
Déclaration de conflit d'intérêts
KP is Founder and Head of the Institute for Research and Innovation. Based at Patras Science Park. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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