title: Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).
abstract: Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Jesen
authors.initials: J
authors.lastname: Fagerness
authors.forename: Robyn
authors.initials: R
authors.lastname: Reynolds
authors.forename: Lucia
authors.initials: L
authors.lastname: Sobrin
authors.forename: Margaret
authors.initials: M
authors.lastname: Parker
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Perciliz L
authors.initials: PL
authors.lastname: Tan
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Oh
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Merriam
authors.forename: Eric
authors.initials: E
authors.lastname: Souied
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.forename: Binxing
authors.initials: B
authors.lastname: Li
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Frederick
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Milam A
authors.initials: MA
authors.lastname: Brantley
authors.forename: Aaron Y
authors.initials: AY
authors.lastname: Lee
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Betsy
authors.initials: B
authors.lastname: Campochiaro
authors.forename: Peter
authors.initials: P
authors.lastname: Campochiaro
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: R Theodore
authors.initials: RT
authors.lastname: Smith
authors.forename: Gaetano R
authors.initials: GR
authors.lastname: Barile
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000378:metabolism; D000090943:Delta-5 Fatty Acid Desaturase; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000502:physiology*; D008055:Lipids / Q000737:chemistry; D008268:Macular Degeneration / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors
chemical_list: D008076:Cholesterol, HDL; D000090943:Delta-5 Fatty Acid Desaturase; C504173:LIPC protein, human; D008055:Lipids; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C000716847:FADS1 protein, human; D008049:Lipase
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