TY - JOUR
T1 - A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)
AU - Grassmann, Felix
AU - Friedrich, Ulrike
AU - Fauser, Sascha
AU - Schick, Tina
AU - Milenkovic, Andrea
AU - Schulz, Heidi L.
AU - von Strachwitz, Claudia N.
AU - Bettecken, Thomas
AU - Lichtner, Peter
AU - Meitinger, Thomas
AU - Arend, Nicole
AU - Wolf, Armin
AU - Haritoglou, Christos
AU - Rudolph, Guenther
AU - Chakravarthy, Usha
AU - Silvestri, Giuliana
AU - McKay, Gareth J.
AU - Freitag-Wolf, Sandra
AU - Krawczak, Michael
AU - Smith, R. Theodore
AU - Merriam, John C.
AU - Merriam, Joanna E.
AU - Allikmets, Rando
AU - Heid, Iris M.
AU - Weber, Bernhard H.F.
N1 - Publisher Copyright:
© 2015, The Author(s).
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Age-related macular degeneration
KW - Canonical DAPL1 isoforms
KW - Death-associated protein-like 1, DAPL1
KW - Genetic association study
UR - http://www.scopus.com/inward/record.url?scp=84939934704&partnerID=8YFLogxK
U2 - 10.1007/s12017-015-8342-1
DO - 10.1007/s12017-015-8342-1
M3 - Article
C2 - 25680934
AN - SCOPUS:84939934704
SN - 1535-1084
VL - 17
SP - 111
EP - 120
JO - NeuroMolecular Medicine
JF - NeuroMolecular Medicine
IS - 2
ER -