title: A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.
abstract: Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.
authors: Department of Ophthalmology, Department of Clinical Chemistry and Hematology.
authors: Jonas J W
authors: JJ
authors: Kuiper
authors: Department of Medical Genetics.
authors: Jessica
authors: J
authors: Van Setten
authors: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: Stephan
authors: S
authors: Ripke
authors: Department of Medical Genetics.
authors: Ruben
authors: R
authors: Van 'T Slot
authors: Department of Medical Genetics.
authors: Flip
authors: F
authors: Mulder
authors: The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors: Tom
authors: T
authors: Missotten
authors: The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors: G Seerp
authors: GS
authors: Baarsma
authors: Department of Medical Genetics.
authors: Laurent C
authors: LC
authors: Francioli
authors: Department of Medical Genetics.
authors: Sara L
authors: SL
authors: Pulit
authors: Department of Medical Genetics.
authors: Carolien G F
authors: CG
authors: De Kovel
authors: Department of Ophthalmology.
authors: Ninette
authors: N
authors: Ten Dam-Van Loon
authors: Department of Ophthalmology and Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors: Anneke I
authors: AI
authors: Den Hollander
authors: Department of Ophthalmology and.
authors: Paulien
authors: P
authors: Huis in het Veld
authors: Department of Ophthalmology and.
authors: Carel B
authors: CB
authors: Hoyng
authors: Unidad de Uveitis. Servicio de Oftalmología, Hospital Universitario de León, León, Spain.
authors: Miguel
authors: M
authors: Cordero-Coma
authors: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN, CSIC, Granada, Spain.
authors: Javier
authors: J
authors: Martín
authors: Institut Clinic d'Oftalmologia (ICOF), Hospital Clinic de Barcelona, Barcelona, Spain.
authors: Victor
authors: V
authors: Llorenç
authors: Moorfields Eye Hospital NHS Foundation Trust, London, UK.
authors: Bharti
authors: B
authors: Arya
authors: Moorfields Eye Hospital NHS Foundation Trust, London, UK.
authors: Dhanes
authors: D
authors: Thomas
authors: Department of Psychiatry, Rudolph Magnus Institute of Neuroscience.
authors: Steven C
authors: SC
authors: Bakker
authors: Department of Psychiatry, Rudolph Magnus Institute of Neuroscience, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA and.
authors: Roel A
authors: RA
authors: Ophoff
authors: Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Aniki
authors: A
authors: Rothova
authors: Department of Medical Genetics, Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Paul I W
authors: PI
authors: De Bakker
authors: Department of Clinical Chemistry and Hematology.
authors: Tuna
authors: T
authors: Mutis
authors: Department of Medical Genetics, B.P.C.Koeleman@umcutrecht.nl.
authors: Bobby P C
authors: BP
authors: Koeleman
mesh_terms: D000483:Alleles; D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism; D000080365:Birdshot Chorioretinopathy; D016022:Case-Control Studies; D002825:Chorioretinitis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D015234:HLA-A Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D044465:White People / Q000235:genetics
chemical_list: D015234:HLA-A Antigens; C035524:HLA-A29 antigen; D000626:Aminopeptidases; C503944:ERAP2 protein, human