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

Abstract

IntroductionAutoimmune 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.MethodsHere, 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.ResultsIn 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.DiscussionOverall, our study confirms the association of different factors with genetic susceptibility for ADs and reveals novel observations that need to be further explored.

Examining the Genetic Links between Clusters of Immune-mediated Diseases and Psychiatric Disorders

“…We began by establishing a factor structure for immune-mediated diseases. Although the genetic factor structure of immune-mediated diseases has previously been investigated, 20,21 we build upon these findings by incorporating additional immune-mediated diseases. Moreover, this updated factor model captures the theoretical continuum of autoimmune and autoinflammatory diseases, which allowed us to examine differential genetic overlap between clusters of psychiatric disorders with diseases characterized by the adaptive versus innate immune system.…”

Technical Report: Protocol for Characterizing Phenotype Variants Using Phenome-Wide Association Study (PheWAS) Utilizing the Nationwide Inpatient Sample 2020 in Individuals With Pancreatic Cysts and Lung Cancer

“…Phenome-wide association studies (PheWAS) represent a powerful approach in the realm of multiphenotype analyses, offering a unique avenue to explore associations between genetic variants and a myriad of phenotypes within a given population [1]. The distinctive strength of PheWAS lies in its capability to associate not only well-known or prevalent phenotypes but also unearth connections with previously unknown or underappreciated health indicators [2,3]. This multifaceted strategy serves to unravel intricate disease mechanisms by mediating phenotypes and can potentially enable the identification of predictive biomarker phenotypes for specific health outcomes [4,5].…”