Search for age-related macular degeneration risk variants in Alzheimer disease genes and pathways.
Several lines of inquiry point to overlapping molecular mechanisms between late-onset Alzheimer disease (AD) and age-related macular degeneration (AMD). We evaluated summarized results from large genome-wide association studies for AD and AMD to test the hypothesis that AD susceptibility loci are also associated with AMD. We observed association of both disorders with genes in a region of chromosome 7, including PILRA and ZCWPW1 (peak AMD SNP rs7792525, minor allele frequency [MAF] = 19%, odds ratio [OR] = 1.14, p = 2.34 × 10(-6)), and with ABCA7 (peak AMD SNP rs3752228, MAF = 0.054, OR = 1.22, p = 0.00012). Next, we evaluated association of AMD with genes in AD-related pathways identified by canonical pathway analysis of AD-associated genes. Significant associations were observed with multiple previously identified AMD risk loci and 2 novel genes: HGS (peak SNP rs8070488, MAF = 0.23, OR = 0.91, p = 7.52 × 10(-5)), which plays a role in the clathrin-mediated endocytosis signaling pathway, and TNF (peak SNP rs2071590, MAF = 0.34, OR = 0.89, p = 1.17 × 10(-5)), which is a member of the atherosclerosis signaling and the LXR/RXR activation pathways. Our results suggest that AMD and AD share genetic mechanisms.
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Mark W
MW
Logue
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Matthew
M
Schu
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Badri N
BN
Vardarajan
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
John
J
Farrell
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Kathryn L
KL
Lunetta
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Gyungah
G
Jun
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Clinton T
CT
Baldwin
John A. Moran Eye Center, University of Utah, Salt Lake City, UT, USA.
Margaret M
MM
Deangelis
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. Electronic address: farrer@bu.edu.
Lindsay A
LA
Farrer
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D002966:Clathrin; D004705:Endocytosis / Q000235:genetics / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D047488:Retinoid X Receptors / Q000378:metabolism; D012306:Risk; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; D002966:Clathrin; D056827:Endosomal Sorting Complexes Required for Transport; D008562:Membrane Glycoproteins; C412263:PILRA protein, human; D010750:Phosphoproteins; D011971:Receptors, Immunologic; D047488:Retinoid X Receptors; D014409:Tumor Necrosis Factor-alpha; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate
Age related macular degeneration; Alzheimer disease; Gene-based test; Genetic association; Pathway analysis