A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)

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• 作者：Felix Grassmann ; Ulrike Friedrich ; Sascha Fauser ; Tina Schick…
• 关键词：Age ; related macular degeneration ; Death ; associated protein ; like 1 ; DAPL1 ; Canonical DAPL1 isoforms ; Genetic association study
• 刊名：NeuroMolecular Medicine
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：17
• 期：2
• 页码：111-120
• 全文大小：941 KB
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• 作者单位：Felix Grassmann (1)
  Ulrike Friedrich (1)
  Sascha Fauser (2)
  Tina Schick (2)
  Andrea Milenkovic (1)
  Heidi L. Schulz (1)
  Claudia N. von Strachwitz (3)
  Thomas Bettecken (4)
  Peter Lichtner (5)
  Thomas Meitinger (5) (6)
  Nicole Arend (7)
  Armin Wolf (7)
  Christos Haritoglou (7)
  Guenther Rudolph (7)
  Usha Chakravarthy (8)
  Giuliana Silvestri (8)
  Gareth J. McKay (9)
  Sandra Freitag-Wolf (10)
  Michael Krawczak (10)
  R. Theodore Smith (11) (12)
  John C. Merriam (11)
  Joanna E. Merriam (11)
  Rando Allikmets (11) (13)
  Iris M. Heid (14)
  Bernhard H. F. Weber (1)
  
  1. Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany
  2. Department of Ophthalmology, University Hospital of Cologne, 53127, Cologne, Germany
  3. EyeCentre Southwest, 70563, Stuttgart, Germany
  4. Max Planck Institute of Psychiatry, 80804, Munich, Germany
  5. Institute of Human Genetics, Helmholtz Zentrum Munich, 85764, Neuherberg, Germany
  6. Institute of Human Genetics, Technical University Munich, 81675, Munich, Germany
  7. University Eye Hospital, Ludwig-Maximilians-University, 80336, Munich, Germany
  8. Centre for Experimental Medicine, Queen’s University of Belfast, Belfast, BT12 6BA, Northern Ireland, UK
  9. Centre for Public Health, Queen’s University of Belfast, Belfast, BT12 6BA, Northern Ireland, UK
  10. Institute of Medical Informatics and Statistics, Christian-Albrechts University, 24105, Kiel, Germany
  11. Department of Ophthalmology, Columbia University, New York, NY, 10032, USA
  12. Department of Ophthalmology, New York University School of Medicine, New York, NY, 10016, USA
  13. Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA
  14. Department of Genetic Epidemiology, University of Regensburg, 93053, Regensburg, Germany
  
• 刊物主题：Neurosciences; Neurology; Internal Medicine;
• 出版者：Springer US
• ISSN：1559-1174

文摘

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50?years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P _ADJ?=?1.15?×?10?, OR 1.332 (1.187-.496)]. This association was characterized by a highly significant sex difference (P _diff?=?0.0032) in that it was clearly confined to females with genome-wide significance [P _ADJ?=?2.62?×?10?, OR 1.541 (1.324-.796); males: P _ADJ?=?0.382, OR 1.084 (0.905-.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis.