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Grassmann, F.* ; Friedrich, U.* ; Fauser, S.* ; Schick, T.* ; Milenkovic, A.* ; Schulz, H.L.* ; von Strachwitz, C.N.* ; Bettecken, T.* ; Lichtner, P. ; Meitinger, T. ; Arend, N.* ; Wolf, A.* ; Haritoglou, C.* ; Rudolph, G.* ; Chakravarthy, U.* ; Silvestri, G.* ; Mckay, G.J.* ; Freitag-Wolf, S.* ; Krawczak, M.* ; Smith, R.* ; Merriam, J.C.* ; Merriam, J.E.* ; Allikmets, R.L.* ; Heid, I.M.* ; Weber, B.H.F.*

A candidate gene association study identifies DAPL1 as a female-specific susceptibility locus for Age-related Macular Degeneration (AMD).

Neuromol. Med. 17, 111-120 (2015)
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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 PADJ = 1.15 × 10−6, OR 1.332 (1.187–1.496)]. This association was characterized by a highly significant sex difference (Pdiff = 0.0032) in that it was clearly confined to females with genome-wide significance [PADJ = 2.62 × 10−8, OR 1.541 (1.324–1.796); males: PADJ = 0.382, OR 1.084 (0.905–1.298)]. 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Age-related Macular Degeneration ; Canonical Dapl1 Isoforms ; Death-associated Protein-like 1, Dapl1 ; Genetic Association Study; Genome-wide Association; Quantitative Traits; Risk; Disease; Protein; Stage; Snp
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 1535-1084
e-ISSN 1559-1174
Zeitschrift Neuromolecular Medicine
Quellenangaben Band: 17, Heft: 2, Seiten: 111-120 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort New York, NY [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
DOI 10.1007/s12017-015-8342-1
WOS ID WOS:000354187600003
Scopus ID 84939934704
Scopus ID 84923064116
Erfassungsdatum 2015-02-26
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