title: Genome-wide association analysis reveals 12q13.3-q14.1 as new risk locus for sarcoidosis.
abstract: Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability. To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages. After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p=0.0215) in the validation panel and yielded a p-value of 9.22 × 10(-8) (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p = 0.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany. s.hofmann@ikmb.uni-kiel.de
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hofmann
authors.forename: Annegret
authors.initials: A
authors.lastname: Fischer
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Gunnar
authors.initials: G
authors.lastname: Jacobs
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schmid
authors.forename: Michael
authors.initials: M
authors.lastname: Wittig
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Karoline I
authors.initials: KI
authors.lastname: Gaede
authors.forename: Manfred
authors.initials: M
authors.lastname: Schürmann
authors.forename: Martin
authors.initials: M
authors.lastname: Petrek
authors.forename: Frantisek
authors.initials: F
authors.lastname: Mrazek
authors.forename: Stefan
authors.initials: S
authors.lastname: Pabst
authors.forename: Christian
authors.initials: C
authors.lastname: Grohé
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
authors.forename: Marcus
authors.initials: M
authors.lastname: Ronninger
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Höhne
authors.forename: Gernot
authors.initials: G
authors.lastname: Zissel
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller-Quernheim
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods; D002881:Chromosomes, Human, Pair 12; D002908:Chronic Disease; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008171:Lung Diseases / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D012507:Sarcoidosis / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D012333:RNA, Messenger