title: Analysis of copy number variation at DMBT1 and age-related macular degeneration.
abstract: DMBT1 is a gene that shows extensive copy number variation (CNV) that alters the number of bacteria-binding domains in the protein and has been shown to activate the complement pathway. It lies next to the ARMS2/HTRA1 genes in a region of chromosome 10q26, where single nucleotide variants have been strongly associated with age-related macular degeneration (AMD), the commonest cause of blindness in Western populations. Complement activation is thought to be a key factor in the pathogenesis of this condition. We sought to investigate whether DMBT1 CNV plays any role in the susceptibility to AMD.
  
  
  
  We analysed long-range linkage disequilibrium of DMBT1 CNV1 and CNV2 with flanking single nucleotide polymorphisms (SNPs) using our previously published CNV and HapMap Phase 3 SNP data in the CEPH Europeans from Utah (CEU). We then typed a large cohort of 860 AMD patients and 419 examined age-matched controls for copy number at DMBT1 CNV1 and CNV2 and combined these data with copy numbers from a further 480 unexamined controls.
  
  
  
  We found weak linkage disequilibrium between DMBT1 CNV1 and CNV2 with the SNPs rs1474526 and rs714816 in the HTRA1/ARMS2 region. By directly analysing copy number variation, we found no evidence of association of CNV1 or CNV2 with AMD.
  
  
  
  We have shown that copy number variation at DMBT1 does not affect risk of developing age-related macular degeneration and can therefore be ruled out from future studies investigating the association of structural variation at 10q26 with AMD.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Shamik
authors.initials: S
authors.lastname: Polley
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.|UCL Genetics Institute, University College London, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cipriani
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge, UK.|Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.|Department of Ophthalmology, Royal Perth Hospital, Perth, Australia.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Khan
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge, UK.|Department of Ophthamology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Humma
authors.initials: H
authors.lastname: Shahid
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.|Moorfields Eye Hospital, London, UK.|Department of Ophthalmology UCSF Medical School, San Francisco, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.|Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: John R W
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK. ejh33@le.ac.uk.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
mesh_terms: D000483:Alleles; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D005787:Gene Frequency; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: C514392:ARMS2 protein, human; D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases