A genome-wide phenotype-overlapping approach for the identification of shared disease loci
Zusammenfassung der Projektergebnisse
Chronic immune-mediated diseases comprise a group of indications with fast growing expenses due to rising incidence and large unmet need. Overlapping etiological genetic factors among immune-mediated diseases have long been suggested because of familial clustering of diseases and co-occurrence in single patients (co-morbidity), and further support has been provided recently by analysis of human leukocyte antigen (HLA) and GWAS studies. We developed different and complementary analysis strategies to identify shared genetic risk loci and, by applying these systematically to large GWAS data sets from major immunemediated diseases (Atopic dermatitis (AD), Crohn’s disease (CD), psoriasis (PS), primary sclerosing cholangitis (PSC) and ulcerative colitis (UC)), we newly identified ‘pleiotropic’ loci shared across different diseases. Most of the newly identified loci can be mapped to a few shared biological pathways, including those related to innate immunity, T-cell activation and cytokine signaling. Moreover, only a few of all risk loci known for immune-mediated disease seem to be unique to a single immune-mediated disease. This raises the question of what determines disease specificity. Interestingly, the genetic architecture at those newly identified shared disease loci seems to be more complex than previously thought. The most associated variant at a given shared locus frequently differs between diseases and might have opposite directions of effects (i.e. risk vs. protective). Redefining disease groups along shared susceptibility genes remains to be challenging and leaves much room for more innovative cross-phenotype studies. The observed opposing effects for associated alleles and/or genes suggest that drug modulating gene products to treat one disease might have unintended adverse effects on another. One known example is the effectiveness of anti-TNF treatments in CD and PS but their counter-effect in multiple sclerosis. The clinical experience with these drugs parallels the recent observation that a SNP associated with multiple sclerosis (but not with CD and PS) in the TNFRSF1A gene, which encodes tumour necrosis factor receptor 1 (TNFR1), mirrors the adverse outcome of anti-TNF therapy in multiple sclerosis. This exemplifies the importance of knowing precisely which genetic factors are shared, unique, protective and risk-increasing and for which disease. Fine mapping and re-sequencing studies but also larger cross-phenotype studies with dozens of different phenotypes and increased samples sizes (including diverse ethnic groups) are needed to discern whether same or different causal alleles are involved and to accurately distinguish between different types of pleiotropy. Further work in the field is warranted because of its potential to inform the development of new diagnostic and therapeutic tools.
Projektbezogene Publikationen (Auswahl)
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Current software for genotype imputation. Hum Genomics. 2009 Jul;3(4):371-80
J. Ellinghaus D, Franke A, Nothnagel M et al.
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A comprehensive evaluation of SNP genotype imputation. Hum Genet. 2009 Mar;125(2):163-71
K. Nothnagel M, Ellinghaus D, Schreiber S, Krawczak M, Franke A
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1000 genomes based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium (WTCCC) phase 1 Data. Eur J Hum Genet. 2012 Jul;20(7):801-5
F. Huang J, Ellinghaus D, Franke A, Howie B, Li Y
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Combined Analysis of Genome-wide Association Studies for Crohn’s Disease and Psoriasis Identifies Seven Shared Susceptibility Loci. Am J Hum Genet. 2012 Apr 6;90(4):636-47
E. Ellinghaus D, Nothnagel M, Franke A et al.
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Genome-wide association analysis in sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology. 2012 Jul 23
D. Ellinghaus D, Franke A, Karlsen TH et al.
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Host-microbe interactions shape genetic risk for inflammatory bowel disease. Nature 2012 Nov 1;491(7422):119-24
I. Jostins L, Ellinghaus D, Franke A, Cho JH et al.
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Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012 Dec;44(12):1341-8. Epub 2012 Nov 11
H. Tsoi LC, Spain SL, Knight J, Ellinghaus E, Franke A, Trembatch RC et al.
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Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies. Gastroenterology. 2013 Apr 25
C. Ellinghaus D, Nothnagel M, Franke A et al.
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Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet. 2013 Apr 21
B. Liu JZ, Franke A, Anderson CA, Karlsen TH et al.
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High density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet. 2013 Jun 2
A. Ellinghaus D, Lee YA, Franke A, Weidinger S et al.
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Pleiotropy in complex traits: challenges and strategies. Nat Rev Genet. 2013 Jul;14(7):483-95
G. Solovieff N, Smoller JW et al.
