Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.
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.
Chen
Wei
W
Center for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
Stambolian
Dwight
D
Edwards
Albert O
AO
Branham
Kari E
KE
Othman
Mohammad
M
Jakobsdottir
Johanna
J
Tosakulwong
Nirubol
N
Pericak-Vance
Margaret A
MA
Campochiaro
Peter A
PA
Klein
Michael L
ML
Tan
Perciliz L
PL
Conley
Yvette P
YP
Kanda
Atsuhiro
A
Kopplin
Laura
L
Li
Yanming
Y
Augustaitis
Katherine J
KJ
Karoukis
Athanasios J
AJ
Scott
William K
WK
Agarwal
Anita
A
Kovach
Jaclyn L
JL
Schwartz
Stephen G
SG
Postel
Eric A
EA
Brooks
Matthew
M
Baratz
Keith H
KH
Brown
William L
WL
Brucker
Alexander J
AJ
Orlin
Anton
A
Brown
Gary
G
Ho
Allen
A
Regillo
Carl
C
Donoso
Larry
L
Tian
Lifeng
L
Kaderli
Brian
B
Hadley
Dexter
D
Hagstrom
Stephanie A
SA
Peachey
Neal S
NS
Klein
Ronald
R
Klein
Barbara E K
BE
Gotoh
Norimoto
N
Yamashiro
Kenji
K
Ferris Iii
Frederick
F
Fagerness
Jesen A
JA
Reynolds
Robyn
R
Farrer
Lindsay A
LA
Kim
Ivana K
IK
Miller
Joan W
JW
Cortón
Marta
M
Carracedo
Angel
A
Sanchez-Salorio
Manuel
M
Pugh
Elizabeth W
EW
Doheny
Kimberly F
KF
Brion
Maria
M
Deangelis
Margaret M
MM
Weeks
Daniel E
DE
Zack
Donald J
DJ
Chew
Emily Y
EY
Heckenlively
John R
JR
Yoshimura
Nagahisa
N
Iyengar
Sudha K
SK
Francis
Peter J
PJ
Katsanis
Nicholas
N
Seddon
Johanna M
JM
Haines
Jonathan L
JL
Gorin
Michael B
MB
Abecasis
Gonçalo R
GR
Swaroop
Anand
A
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
D008075:Lipoproteins, HDL; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D017244:Complement Factor I
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