title: Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.
abstract: We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.
authors.affiliation: Center for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Dwight
authors.initials: D
authors.lastname: Stambolian
authors.forename: Albert O
authors.initials: AO
authors.lastname: Edwards
authors.forename: Kari E
authors.initials: KE
authors.lastname: Branham
authors.forename: Mohammad
authors.initials: M
authors.lastname: Othman
authors.forename: Johanna
authors.initials: J
authors.lastname: Jakobsdottir
authors.forename: Nirubol
authors.initials: N
authors.lastname: Tosakulwong
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
authors.forename: Perciliz L
authors.initials: PL
authors.lastname: Tan
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kanda
authors.forename: Laura
authors.initials: L
authors.lastname: Kopplin
authors.forename: Yanming
authors.initials: Y
authors.lastname: Li
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Augustaitis
authors.forename: Athanasios J
authors.initials: AJ
authors.lastname: Karoukis
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Anita
authors.initials: A
authors.lastname: Agarwal
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Kovach
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Schwartz
authors.forename: Eric A
authors.initials: EA
authors.lastname: Postel
authors.forename: Matthew
authors.initials: M
authors.lastname: Brooks
authors.forename: Keith H
authors.initials: KH
authors.lastname: Baratz
authors.forename: William L
authors.initials: WL
authors.lastname: Brown
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Brucker
authors.forename: Anton
authors.initials: A
authors.lastname: Orlin
authors.forename: Gary
authors.initials: G
authors.lastname: Brown
authors.forename: Allen
authors.initials: A
authors.lastname: Ho
authors.forename: Carl
authors.initials: C
authors.lastname: Regillo
authors.forename: Larry
authors.initials: L
authors.lastname: Donoso
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.forename: Brian
authors.initials: B
authors.lastname: Kaderli
authors.forename: Dexter
authors.initials: D
authors.lastname: Hadley
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Hagstrom
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.forename: Barbara E K
authors.initials: BE
authors.lastname: Klein
authors.forename: Norimoto
authors.initials: N
authors.lastname: Gotoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamashiro
authors.forename: Frederick
authors.initials: F
authors.lastname: Ferris Iii
authors.forename: Jesen A
authors.initials: JA
authors.lastname: Fagerness
authors.forename: Robyn
authors.initials: R
authors.lastname: Reynolds
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Ivana K
authors.initials: IK
authors.lastname: Kim
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Marta
authors.initials: M
authors.lastname: Cortón
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez-Salorio
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Pugh
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: Maria
authors.initials: M
authors.lastname: Brion
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Deangelis
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Francis
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gorin
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping; D017244:Complement Factor I / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008268:Macular Degeneration / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012306:Risk; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000502:physiology
chemical_list: D008075:Lipoproteins, HDL; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D017244:Complement Factor I
references.citation: Annu Rev Genomics Hum Genet. 2009;10:19-43
references.pmid: 19405847
references.citation: Hum Mol Genet. 2005 Aug 1;14(15):2257-64
references.pmid: 15987700
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7395-400
references.pmid: 20385826
references.citation: Exp Eye Res. 2005 Dec;81(6):731-41
references.pmid: 16005869
references.citation: Nat Genet. 2008 May;40(5):638-45
references.pmid: 18372903
references.citation: Eur J Hum Genet. 2009 Jan;17(1):100-4
references.pmid: 18685559
references.citation: PLoS Genet. 2009 Feb;5(2):e1000337
references.pmid: 19197355
references.citation: N Engl J Med. 2007 Aug 9;357(6):553-61
references.pmid: 17634448
references.citation: Hum Mol Genet. 2005 Nov 1;14(21):3227-36
references.pmid: 16174643
references.citation: Nat Genet. 2008 Aug;40(8):955-62
references.pmid: 18587394
references.citation: Ophthalmology. 1993 Mar;100(3):406-14
references.pmid: 8460013
references.citation: Nat Genet. 2009 Jan;41(1):25-34
references.pmid: 19079261
references.citation: Nat Genet. 2007 Oct;39(10):1200-1
references.pmid: 17767156
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Science. 2006 Nov 10;314(5801):989-92
references.pmid: 17053108
references.citation: Nat Genet. 2006 Sep;38(9):1055-9
references.pmid: 16936732
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16227-32
references.pmid: 17884985
references.citation: Science. 2005 Apr 15;308(5720):419-21
references.pmid: 15761120
references.citation: Nat Genet. 2009 Feb;41(2):199-204
references.pmid: 19169254
references.citation: Science. 2005 Apr 15;308(5720):385-9
references.pmid: 15761122
references.citation: Am J Hum Genet. 2007 Aug;81(2):321-37
references.pmid: 17668381
references.citation: Nat Genet. 2009 Jan;41(1):56-65
references.pmid: 19060906
references.citation: Nat Genet. 2006 Sep;38(9):1049-54
references.pmid: 16936733
references.citation: Am J Hum Genet. 2005 Sep;77(3):389-407
references.pmid: 16080115
references.citation: Biometrics. 1999 Dec;55(4):997-1004
references.pmid: 11315092
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: Nat Genet. 2006 Apr;38(4):458-62
references.pmid: 16518403
references.citation: Ophthalmology. 2004 Jul;111(7):1280-7
references.pmid: 15234127
references.citation: Nat Genet. 1994 Dec;8(4):352-6
references.pmid: 7894485
references.citation: Science. 2005 Apr 15;308(5720):421-4
references.pmid: 15761121
references.citation: Am J Hum Genet. 2004 Mar;74(3):482-94
references.pmid: 14968411
references.citation: Am J Hum Genet. 2001 Dec;69(6):1357-69
references.pmid: 11593451
references.citation: FASEB J. 2000 May;14(7):835-46
references.pmid: 10783137
references.citation: J Neurosci. 2002 Jun 1;22(11):4372-80
references.pmid: 12040043
references.citation: PLoS Genet. 2008 Jan;4(1):e4
references.pmid: 18208329
references.citation: Nat Genet. 2008 Feb;40(2):161-9
references.pmid: 18193043