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

Felix Grassmann; Ulrike Friedrich; Sascha Fauser; Tina Schick; Andrea Milenkovic; Heidi L. Schulz; Claudia N. von Strachwitz; Thomas Bettecken; Peter Lichtner; Thomas Meitinger; Nicole Arend; Armin Wolf; Christos Haritoglou; Guenther Rudolph; Usha Chakravarthy; Giuliana Silvestri; Gareth J. McKay; Sandra Freitag-Wolf; Michael Krawczak; R. Theodore Smith; John C. Merriam; Joanna E. Merriam; Rando Allikmets; Iris M. Heid; Bernhard H.F. Weber

doi:10.1007/s12017-015-8342-1

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

Felix Grassmann, Ulrike Friedrich, Sascha Fauser, Tina Schick, Andrea Milenkovic, Heidi L. Schulz, Claudia N. von Strachwitz, Thomas Bettecken, Peter Lichtner, Thomas Meitinger, Nicole Arend, Armin Wolf, Christos Haritoglou, Guenther Rudolph, Usha Chakravarthy, Giuliana Silvestri, Gareth J. McKay, Sandra Freitag-Wolf, Michael Krawczak, R. Theodore SmithJohn C. Merriam, Joanna E. Merriam, Rando Allikmets, Iris M. Heid, Bernhard H.F. Weber^*

^*Corresponding author for this work

Medical Sciences

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

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 P_ADJ = 1.15 × 10⁻⁶, OR 1.332 (1.187–1.496)]. 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 × 10⁻⁸, OR 1.541 (1.324–1.796); males: P_ADJ = 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.

Original language	English
Pages (from-to)	111-120
Number of pages	10
Journal	NeuroMolecular Medicine
Volume	17
Issue number	2
DOIs	https://doi.org/10.1007/s12017-015-8342-1
Publication status	Published - 1 Jun 2015

Bibliographical note

Acknowledgments
We thank all patients and control individuals for their participation in the study, Kerstin Meier and Jürgen Kaschkötö (Institute of Human Genetics, University of Regensburg) for technical support, and Lars G. Fritsche (Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan) and Thomas Winkler (Institute of Epidemiology, University of Regensburg, Regensburg) for help with computational tools and data analysis. This study was supported partly by the Deutsche Forschungsgemeinschaft (WE 1259/19-1 and WE 1259/19-2 to BHFW), the Alcon Research Institute (to BHFW and RA), by grants from the National Eye Institute/NIH EY013435 and EY019007 (to RA); the Macula Vision Research Foundation (to RA); an unrestricted grant to the Department of Ophthalmology, Columbia University, from Research to Prevent Blindness, Inc. (to RA), and the Guide Dogs for the Blind Association UK (2008-5a) Macular Disease Society (to US, GS, GJM).

Data Availability Statement

Electronic supplementary material is available within the article links

Keywords

Age-related macular degeneration
Canonical DAPL1 isoforms
Death-associated protein-like 1, DAPL1
Genetic association study

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10.1007/s12017-015-8342-1

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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., ... Weber, B. H. F. (2015). A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD). NeuroMolecular Medicine, 17(2), 111-120. https://doi.org/10.1007/s12017-015-8342-1

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, BHF 2015, 'A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)', NeuroMolecular Medicine, vol. 17, no. 2, pp. 111-120. https://doi.org/10.1007/s12017-015-8342-1

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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.",

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author = "Felix Grassmann and Ulrike Friedrich and Sascha Fauser and Tina Schick and Andrea Milenkovic and Schulz, {Heidi L.} and {von Strachwitz}, {Claudia N.} and Thomas Bettecken and Peter Lichtner and Thomas Meitinger and Nicole Arend and Armin Wolf and Christos Haritoglou and Guenther Rudolph and Usha Chakravarthy and Giuliana Silvestri and McKay, {Gareth J.} and Sandra Freitag-Wolf and Michael Krawczak and Smith, {R. Theodore} and Merriam, {John C.} and Merriam, {Joanna E.} and Rando Allikmets and Heid, {Iris M.} and Weber, {Bernhard H.F.}",

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AU - Milenkovic, Andrea

AU - Schulz, Heidi L.

AU - von Strachwitz, Claudia N.

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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.

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

Access to Document

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