RATIONALE: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. OBJECTIVES: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genome-wide association scan for these phenotypes. METHODS: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. MEASUREMENTS AND MAIN RESULTS: We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 × 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. CONCLUSIONS: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis.
RATIONALE: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. OBJECTIVES: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genome-wide association scan for these phenotypes. METHODS: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. MEASUREMENTS AND MAIN RESULTS: We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 × 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. CONCLUSIONS: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis.
Authors: Annegret Fischer; David Ellinghaus; Marcel Nutsua; Sylvia Hofmann; Courtney G Montgomery; Michael C Iannuzzi; Benjamin A Rybicki; Martin Petrek; Frantisek Mrazek; Stefan Pabst; Christian Grohé; Johan Grunewald; Marcus Ronninger; Anders Eklund; Leonid Padyukov; Violeta Mihailovic-Vucinic; Dragana Jovanovic; Martina Sterclova; Jiri Homolka; Markus M Nöthen; Stefan Herms; Christian Gieger; Konstantin Strauch; Juliane Winkelmann; Bernhard O Boehm; Stephan Brand; Carsten Büning; Manfred Schürmann; Eva Ellinghaus; Hansjörg Baurecht; Wolfgang Lieb; Almut Nebel; Joachim Müller-Quernheim; Andre Franke; Stefan Schreiber Journal: Am J Respir Crit Care Med Date: 2015-09-15 Impact factor: 21.405
Authors: Daniel S Tylee; Jiayin Sun; Jonathan L Hess; Muhammad A Tahir; Esha Sharma; Rainer Malik; Bradford B Worrall; Andrew J Levine; Jeremy J Martinson; Sergey Nejentsev; Doug Speed; Annegret Fischer; Eric Mick; Brian R Walker; Andrew Crawford; Struan F A Grant; Constantin Polychronakos; Jonathan P Bradfield; Patrick M A Sleiman; Hakon Hakonarson; Eva Ellinghaus; James T Elder; Lam C Tsoi; Richard C Trembath; Jonathan N Barker; Andre Franke; Abbas Dehghan; Stephen V Faraone; Stephen J Glatt Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2018-10-16 Impact factor: 3.568
Authors: Ole A Andreassen; Rahul S Desikan; Yunpeng Wang; Wesley K Thompson; Andrew J Schork; Verena Zuber; Nadezhda T Doncheva; Eva Ellinghaus; Mario Albrecht; Morten Mattingsdal; Andre Franke; Benedicte A Lie; Ian G Mills; Ian Mills; Pål Aukrust; Linda K McEvoy; Srdjan Djurovic; Tom H Karlsen; Anders M Dale Journal: PLoS One Date: 2015-04-08 Impact factor: 3.240