Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide

Summary: Because transethnic analysis may facilitate prioritization of causal genetic variants, we performed a genome-wide association study (GWAS) of psoriasis in South Asians (SAS), consisting of 2,590 cases and 1,720 controls. Comparison with our existing European-origin (EUR) GWAS showed that ef...

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Autores principales:	Philip E. Stuart, Lam C. Tsoi, Rajan P. Nair, Manju Ghosh, Madhulika Kabra, Pakeeza A. Shaiq, Ghazala K. Raja, Raheel Qamar, B.K. Thelma, Matthew T. Patrick, Anita Parihar, Sonam Singh, Sujay Khandpur, Uma Kumar, Michael Wittig, Frauke Degenhardt, Trilokraj Tejasvi, John J. Voorhees, Stephan Weidinger, Andre Franke, Goncalo R. Abecasis, Vinod K. Sharma, James T. Elder
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	genome-wide association study major histocompatibility complex human leukocyte antigens imputation psoriasis skin diseases Genetics QH426-470
Acceso en línea:	https://doaj.org/article/5428a1ebeaa24b259fb5e47d9912fd38
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spelling	oai:doaj.org-article:5428a1ebeaa24b259fb5e47d9912fd382021-11-22T04:31:04ZTransethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide2666-247710.1016/j.xhgg.2021.100069https://doaj.org/article/5428a1ebeaa24b259fb5e47d9912fd382022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2666247721000506https://doaj.org/toc/2666-2477Summary: Because transethnic analysis may facilitate prioritization of causal genetic variants, we performed a genome-wide association study (GWAS) of psoriasis in South Asians (SAS), consisting of 2,590 cases and 1,720 controls. Comparison with our existing European-origin (EUR) GWAS showed that effect sizes of known psoriasis signals were highly correlated in SAS and EUR (Spearman ρ = 0.78; p < 2 × 10−14). Transethnic meta-analysis identified two non-major histocompatibility complex (non-MHC) psoriasis loci (1p36.22 and 1q24.2) not previously identified in EUR, which may have regulatory roles. For these two loci, the transethnic GWAS provided higher genetic resolution and reduced the number of potential causal variants compared to using the EUR sample alone. We then explored multiple strategies to develop reference panels for accurately imputing MHC genotypes in both SAS and EUR populations and conducted a fine mapping of MHC psoriasis associations in SAS and the largest such effort for EUR. HLA-C∗06 was the top-ranking MHC locus in both populations but was even more prominent in SAS based on odds ratio, disease liability, model fit, and predictive power. Transethnic modeling also substantially boosted the probability that the HLA-C∗06 protein variant is causal. Secondary MHC signals included coding variants of HLA-C and HLA-B, but also potential regulatory variants of these two genes as well as HLA-A and several HLA class II genes, with effects on both chromatin accessibility and gene expression. This study highlights the shared genetic basis of psoriasis in SAS and EUR populations and the value of transethnic meta-analysis for discovery and fine mapping of susceptibility loci.Philip E. StuartLam C. TsoiRajan P. NairManju GhoshMadhulika KabraPakeeza A. ShaiqGhazala K. RajaRaheel QamarB.K. ThelmaMatthew T. PatrickAnita PariharSonam SinghSujay KhandpurUma KumarMichael WittigFrauke DegenhardtTrilokraj TejasviJohn J. VoorheesStephan WeidingerAndre FrankeGoncalo R. AbecasisVinod K. SharmaJames T. ElderElsevierarticlegenome-wide association studymajor histocompatibility complexhuman leukocyte antigensimputationpsoriasisskin diseasesGeneticsQH426-470ENHGG Advances, Vol 3, Iss 1, Pp 100069- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	genome-wide association study major histocompatibility complex human leukocyte antigens imputation psoriasis skin diseases Genetics QH426-470
spellingShingle	genome-wide association study major histocompatibility complex human leukocyte antigens imputation psoriasis skin diseases Genetics QH426-470 Philip E. Stuart Lam C. Tsoi Rajan P. Nair Manju Ghosh Madhulika Kabra Pakeeza A. Shaiq Ghazala K. Raja Raheel Qamar B.K. Thelma Matthew T. Patrick Anita Parihar Sonam Singh Sujay Khandpur Uma Kumar Michael Wittig Frauke Degenhardt Trilokraj Tejasvi John J. Voorhees Stephan Weidinger Andre Franke Goncalo R. Abecasis Vinod K. Sharma James T. Elder Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide
description	Summary: Because transethnic analysis may facilitate prioritization of causal genetic variants, we performed a genome-wide association study (GWAS) of psoriasis in South Asians (SAS), consisting of 2,590 cases and 1,720 controls. Comparison with our existing European-origin (EUR) GWAS showed that effect sizes of known psoriasis signals were highly correlated in SAS and EUR (Spearman ρ = 0.78; p < 2 × 10−14). Transethnic meta-analysis identified two non-major histocompatibility complex (non-MHC) psoriasis loci (1p36.22 and 1q24.2) not previously identified in EUR, which may have regulatory roles. For these two loci, the transethnic GWAS provided higher genetic resolution and reduced the number of potential causal variants compared to using the EUR sample alone. We then explored multiple strategies to develop reference panels for accurately imputing MHC genotypes in both SAS and EUR populations and conducted a fine mapping of MHC psoriasis associations in SAS and the largest such effort for EUR. HLA-C∗06 was the top-ranking MHC locus in both populations but was even more prominent in SAS based on odds ratio, disease liability, model fit, and predictive power. Transethnic modeling also substantially boosted the probability that the HLA-C∗06 protein variant is causal. Secondary MHC signals included coding variants of HLA-C and HLA-B, but also potential regulatory variants of these two genes as well as HLA-A and several HLA class II genes, with effects on both chromatin accessibility and gene expression. This study highlights the shared genetic basis of psoriasis in SAS and EUR populations and the value of transethnic meta-analysis for discovery and fine mapping of susceptibility loci.
format	article
author	Philip E. Stuart Lam C. Tsoi Rajan P. Nair Manju Ghosh Madhulika Kabra Pakeeza A. Shaiq Ghazala K. Raja Raheel Qamar B.K. Thelma Matthew T. Patrick Anita Parihar Sonam Singh Sujay Khandpur Uma Kumar Michael Wittig Frauke Degenhardt Trilokraj Tejasvi John J. Voorhees Stephan Weidinger Andre Franke Goncalo R. Abecasis Vinod K. Sharma James T. Elder
author_facet	Philip E. Stuart Lam C. Tsoi Rajan P. Nair Manju Ghosh Madhulika Kabra Pakeeza A. Shaiq Ghazala K. Raja Raheel Qamar B.K. Thelma Matthew T. Patrick Anita Parihar Sonam Singh Sujay Khandpur Uma Kumar Michael Wittig Frauke Degenhardt Trilokraj Tejasvi John J. Voorhees Stephan Weidinger Andre Franke Goncalo R. Abecasis Vinod K. Sharma James T. Elder
author_sort	Philip E. Stuart
title	Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide
title_short	Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide
title_full	Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide
title_fullStr	Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide
title_full_unstemmed	Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide
title_sort	transethnic analysis of psoriasis susceptibility in south asians and europeans enhances fine mapping in the mhc and genome wide
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/5428a1ebeaa24b259fb5e47d9912fd38
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Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide

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