Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci

Abstract

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 3 10 À8 ) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p rs1250544 ¼ 3.53 3 10 À8 , 11q13 near PRDX5, p rs694739 ¼ 3.71 3 10 À09 , 22q11 at YDJC, p rs181359 ¼ 8.02 3 10 À10 ). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p rs4780355 ¼ 4.99 3 10 À8 ). Refinement of association signals identified shared genomewide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.

Sequencing-based approach identified three new susceptibility loci for psoriasis

“…Our understanding of the genetic architecture of psoriasis has increased rapidly due to genome-wide association studies (GWASs), which have identified more than 40 psoriasis susceptibility genes/loci [2][3][4][5][6][7][8][9][10][11][12][13] . However, the combined effect of these loci does not fully account for the observed genetic susceptibility to psoriasis, indicating that additional genetic factors remain to be discovered.…”

Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to psoriasis in a Chinese population

“…3 During the past five years, genome-wide association studies (GWAS), primarily based on single nucleotide polymorphism markers, have identified many loci as potential psoriasis susceptibility regions. 4,5 Angiotensin-converting enzyme (ACE) is an important circulating enzyme in the renin-angiotensin-aldosterone system (RAAS). 6 ACE is expressed in a wide range of tissues including skin, vascular endothelium and immune cells.…”

Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population

“…6 Large epidemiological studies have shown that the higher incidence of psoriasis in patients with schizophrenia and even in individuals with a family history of schizophrenia in both Chinese and European populations. [7][8][9][10]20 While we demonstrated a shared genetic etiology between these diseases, common environmental factors may still play a role in the disease coetiologies (e.g., stress event in epidemiological studies). 38,39 The additional role of environmental factors and how such environmental factors may influence genetic factors (i.e., gene × environment interactions) remains to be explored.…”

“…[16][17][18] Given that most common disorders and traits have been shown to have a polygenic basis, many researchers have explored the possibility that many complex disorders and traits, including schizophrenia and psoriasis, actually share genetic determinants (i.e., are genetically correlated to some degree). [19][20][21][22][23][24][25][26] This trend appears to be even more pronounced in diseases of autoimmune origin. 27 In this light, we tested our hypothesis of a shared genetic basis of schizophrenia and psoriasis using large cohorts previously studied in independent GWAS.…”