PheWAS and cross-disorder analysis reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders

Apostolia Topaloudi; Pritesh Jain; Melanie B Martinez; Josephine K Bryant; Grace Reynolds; Zoi Zagoriti; George Lagoumintzis; Eleni Zamba-Papanicolaou; John Tzartos; Konstantinos Poulas; Kleopas A Kleopa; Socrates Tzartos; Marianthi Georgitsi; Petros Drineas; Peristera Paschou

doi:10.3389/fimmu.2023.1147573

PheWAS and cross-disorder analysis reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders

Front Immunol. 2023 Sep 21:14:1147573. doi: 10.3389/fimmu.2023.1147573. eCollection 2023.

Authors

Apostolia Topaloudi¹, Pritesh Jain¹, Melanie B Martinez¹, Josephine K Bryant¹, Grace Reynolds^{1

2}, Zoi Zagoriti³, George Lagoumintzis³, Eleni Zamba-Papanicolaou⁴, John Tzartos⁵, Konstantinos Poulas³, Kleopas A Kleopa⁶, Socrates Tzartos^{3

7}, Marianthi Georgitsi⁸, Petros Drineas⁹, Peristera Paschou¹

Affiliations

¹ Department of Biological Sciences, Purdue University, West Lafayette, IN, United States.
² West Lafayette High School, West Lafayette, IN, United States.
³ Department of Pharmacy, University of Patras, Rio, Greece.
⁴ Department of Neuroepidemiology and Centre for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
⁵ B' Neurology Department, School of Medicine, National & Kapodistrian University of Athens, "Attikon" University Hospital., Athens, Greece.
⁶ Department of Neuroscience and Centre for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
⁷ Tzartos NeuroDiagnostics, Athens, Greece.
⁸ Department of Molecular Biology and Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupoli, Greece.
⁹ Department of Computer Science, Purdue University, West Lafayette, IN, United States.

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: Overall, our study confirms the association of different factors with genetic susceptibility for ADs and reveals novel observations that need to be further explored.

Keywords: GWAS; PRS; PheWAS; autoimmune disorders; cross-disorder; meta-analysis.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Autoimmune Diseases* / genetics
Diabetes Mellitus, Type 1* / genetics
HLA Antigens
Humans
Phenotype
Polymorphism, Single Nucleotide
Vitiligo*

Substances

HLA Antigens