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

Grassmann F, Friedrich U, Fauser S, Schick T, Milenkovic A, Schulz HL, von Strachwitz CN, Bettecken T, Lichtner P, Meitinger T, Arend N, Wolf A, Haritoglou C, Rudolph G, Chakravarthy U, Silvestri G, McKay GJ, Freitag-Wolf S, Krawczak M, Smith RT, Merriam JC, Merriam JE, Allikmets R, Heid IM, Weber BH - Neuromolecular Med. (2015)

Bottom Line: 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)].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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Subgroup analysis in the combined study of candidate SNPs rs17810398 and rs17810816 in the DAPL1 gene. OR and corresponding 95 % confidence intervals are given with the size of each rectangles representing the respective number of cases. AMD phenotypic subgroups comprise patients with geographic atrophy (GA), and neovascular AMD (NV) and both late stage forms (GA&NV)
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Fig2: Subgroup analysis in the combined study of candidate SNPs rs17810398 and rs17810816 in the DAPL1 gene. OR and corresponding 95 % confidence intervals are given with the size of each rectangles representing the respective number of cases. AMD phenotypic subgroups comprise patients with geographic atrophy (GA), and neovascular AMD (NV) and both late stage forms (GA&NV)

Mentions: Stratifying the combined analysis by phenotype, including AMD subtype and age-group, revealed no subgroup-specific association for rs17810398 or rs17810816 (Fig. 2). However, stratification by sex revealed that the association signals of both SNPs were confined to females with genome-wide significance (rs1710398: PADJ = 2.62 × 10−8, rs17810816: PADJ = 2.68 × 10−8). No AMD association was evident in males (rs1710398: PADJ = 0.382, rs17810816: PADJ = 0.141; Fig. 2, Supplementary Figure S2; Table 2). The difference between sex-specific ORs was statistically significant (rs17810398: Pdiff = 0.0034, rs17810816: Pdiff = 0.014) at the 5 % level and was observed in all studies analyzed (Supplementary Figure S2; Table 2). In the combined study, the minor allele frequency (MAF) of rs17810398 was lower in female controls than in male controls and higher in female cases than in male cases. A similar, albeit less pronounced effect was seen for variant rs17810816.Fig. 2


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

Grassmann F, Friedrich U, Fauser S, Schick T, Milenkovic A, Schulz HL, von Strachwitz CN, Bettecken T, Lichtner P, Meitinger T, Arend N, Wolf A, Haritoglou C, Rudolph G, Chakravarthy U, Silvestri G, McKay GJ, Freitag-Wolf S, Krawczak M, Smith RT, Merriam JC, Merriam JE, Allikmets R, Heid IM, Weber BH - Neuromolecular Med. (2015)

Subgroup analysis in the combined study of candidate SNPs rs17810398 and rs17810816 in the DAPL1 gene. OR and corresponding 95 % confidence intervals are given with the size of each rectangles representing the respective number of cases. AMD phenotypic subgroups comprise patients with geographic atrophy (GA), and neovascular AMD (NV) and both late stage forms (GA&NV)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4419162&req=5

Fig2: Subgroup analysis in the combined study of candidate SNPs rs17810398 and rs17810816 in the DAPL1 gene. OR and corresponding 95 % confidence intervals are given with the size of each rectangles representing the respective number of cases. AMD phenotypic subgroups comprise patients with geographic atrophy (GA), and neovascular AMD (NV) and both late stage forms (GA&NV)
Mentions: Stratifying the combined analysis by phenotype, including AMD subtype and age-group, revealed no subgroup-specific association for rs17810398 or rs17810816 (Fig. 2). However, stratification by sex revealed that the association signals of both SNPs were confined to females with genome-wide significance (rs1710398: PADJ = 2.62 × 10−8, rs17810816: PADJ = 2.68 × 10−8). No AMD association was evident in males (rs1710398: PADJ = 0.382, rs17810816: PADJ = 0.141; Fig. 2, Supplementary Figure S2; Table 2). The difference between sex-specific ORs was statistically significant (rs17810398: Pdiff = 0.0034, rs17810816: Pdiff = 0.014) at the 5 % level and was observed in all studies analyzed (Supplementary Figure S2; Table 2). In the combined study, the minor allele frequency (MAF) of rs17810398 was lower in female controls than in male controls and higher in female cases than in male cases. A similar, albeit less pronounced effect was seen for variant rs17810816.Fig. 2

Bottom Line: 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)].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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus