Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide
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
Affiliations
Philip E. Stuart
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA
Lam C. Tsoi
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor MI, USA
Rajan P. Nair
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA
Manju Ghosh
Department of Pediatrics Genetics, All India Institute of Medical Sciences, New Delhi, India
Madhulika Kabra
Department of Pediatrics Genetics, All India Institute of Medical Sciences, New Delhi, India
Pakeeza A. Shaiq
Department of Biochemistry, PMASAA University, Rawalpindi, Pakistan
Ghazala K. Raja
Department of Biochemistry, PMASAA University, Rawalpindi, Pakistan
Raheel Qamar
COMSATS Institute of Information Technology, Islamabad, Pakistan
B.K. Thelma
Department of Genetics, University of Delhi South Campus, 110021 New Delhi, India
Matthew T. Patrick
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA
Anita Parihar
Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
Sonam Singh
Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
Sujay Khandpur
Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
Uma Kumar
Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India
Michael Wittig
Institute of Clinical Molecular Biology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany
Frauke Degenhardt
Institute of Clinical Molecular Biology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany
Trilokraj Tejasvi
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA
John J. Voorhees
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA
Stephan Weidinger
Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany
Andre Franke
Institute of Clinical Molecular Biology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany
Goncalo R. Abecasis
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
Vinod K. Sharma
Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
James T. Elder
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USA; Corresponding author
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.
