PMID- 37809097 OWN - NLM STAT- MEDLINE DCOM- 20231103 LR - 20231103 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - PheWAS and cross-disorder analysis reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders. PG - 1147573 LID - 10.3389/fimmu.2023.1147573 [doi] LID - 1147573 AB - 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. CI - Copyright (c) 2023 Topaloudi, Jain, Martinez, Bryant, Reynolds, Zagoriti, Lagoumintzis, Zamba-Papanicolaou, Tzartos, Poulas, Kleopa, Tzartos, Georgitsi, Drineas and Paschou. FAU - Topaloudi, Apostolia AU - Topaloudi A AD - Department of Biological Sciences, Purdue University, West Lafayette, IN, United States. FAU - Jain, Pritesh AU - Jain P AD - Department of Biological Sciences, Purdue University, West Lafayette, IN, United States. FAU - Martinez, Melanie B AU - Martinez MB AD - Department of Biological Sciences, Purdue University, West Lafayette, IN, United States. FAU - Bryant, Josephine K AU - Bryant JK AD - Department of Biological Sciences, Purdue University, West Lafayette, IN, United States. FAU - Reynolds, Grace AU - Reynolds G AD - Department of Biological Sciences, Purdue University, West Lafayette, IN, United States. AD - West Lafayette High School, West Lafayette, IN, United States. FAU - Zagoriti, Zoi AU - Zagoriti Z AD - Department of Pharmacy, University of Patras, Rio, Greece. FAU - Lagoumintzis, George AU - Lagoumintzis G AD - Department of Pharmacy, University of Patras, Rio, Greece. FAU - Zamba-Papanicolaou, Eleni AU - Zamba-Papanicolaou E AD - Department of Neuroepidemiology and Centre for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. FAU - Tzartos, John AU - Tzartos J AD - B' Neurology Department, School of Medicine, National & Kapodistrian University of Athens, "Attikon" University Hospital., Athens, Greece. FAU - Poulas, Konstantinos AU - Poulas K AD - Department of Pharmacy, University of Patras, Rio, Greece. FAU - Kleopa, Kleopas A AU - Kleopa KA AD - Department of Neuroscience and Centre for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. FAU - Tzartos, Socrates AU - Tzartos S AD - Department of Pharmacy, University of Patras, Rio, Greece. AD - Tzartos NeuroDiagnostics, Athens, Greece. FAU - Georgitsi, Marianthi AU - Georgitsi M AD - Department of Molecular Biology and Genetics, School of Health Sciences, Democritus University of Thrace, Alexandroupoli, Greece. FAU - Drineas, Petros AU - Drineas P AD - Department of Computer Science, Purdue University, West Lafayette, IN, United States. FAU - Paschou, Peristera AU - Paschou P AD - Department of Biological Sciences, Purdue University, West Lafayette, IN, United States. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't DEP - 20230921 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (HLA Antigens) SB - IM MH - Humans MH - *Autoimmune Diseases/genetics MH - *Diabetes Mellitus, Type 1/genetics MH - HLA Antigens MH - Phenotype MH - Polymorphism, Single Nucleotide MH - *Vitiligo PMC - PMC10552152 OTO - NOTNLM OT - GWAS OT - PRS OT - PheWAS OT - autoimmune disorders OT - cross-disorder OT - meta-analysis COIS- 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. EDAT- 2023/10/09 06:42 MHDA- 2023/11/01 12:43 PMCR- 2023/01/01 CRDT- 2023/10/09 05:51 PHST- 2023/01/18 00:00 [received] PHST- 2023/09/04 00:00 [accepted] PHST- 2023/11/01 12:43 [medline] PHST- 2023/10/09 06:42 [pubmed] PHST- 2023/10/09 05:51 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1147573 [doi] PST - epublish SO - Front Immunol. 2023 Sep 21;14:1147573. doi: 10.3389/fimmu.2023.1147573. eCollection 2023.