Genetic variants near
TIMP3
and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration
Authors: Chen Wei , Stambolian Dwight , Edwards Albert O. , Branham Kari E. , Othman Mohammad , Jakobsdottir Johanna , Tosakulwong Nirubol , Pericak-Vance Margaret A. , Campochiaro Peter A. , Klein Michael L. , Tan Perciliz L. , Conley Yvette P. , Kanda Atsuhiro , Kopplin Laura , Li Yanming , Augustaitis Katherine J. , Karoukis Athanasios J. , Scott William K. , Agarwal Anita , Kovach Jaclyn L. , Schwartz Stephen G. , Postel Eric A. , Brooks Matthew , Baratz Keith H. , Brown William L. ,   Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Group, Brucker Alexander J. , Orlin Anton , Brown Gary , Ho Allen , Regillo Carl , Donoso Larry , Tian Lifeng , Kaderli Brian , Hadley Dexter , Hagstrom Stephanie A. , Peachey Neal S. , Klein Ronald , Klein Barbara E. K. , Gotoh Norimoto , Yamashiro Kenji , Ferris Frederick , Fagerness Jesen A. , Reynolds Robyn , Farrer Lindsay A. , Kim Ivana K. , Miller Joan W. , Cortón Marta , Carracedo Angel , Sanchez-Salorio Manuel , Pugh Elizabeth W. , Doheny Kimberly F. , Brion Maria , DeAngelis Margaret M. , Weeks Daniel E. , Zack Donald J. , Chew Emily Y. , Heckenlively John R. , Yoshimura Nagahisa , Iyengar Sudha K. , Francis Peter J. , Katsanis Nicholas , Seddon Johanna M. , Haines Jonathan L. , Gorin Michael B. , Abecasis Gonçalo R. , Swaroop Anand , Johnson Robert N. , Ai Everett , McDonald H. Richard , Stolarczuk Margaret , Pavan Peter Reed , Billiris Karina K. , Iyer Mohan , Menosky Matthew M. , Pautler Scott E. , Millard Sharon M. , Hubbard Baker , Aaberg Thomas , DuBois Lindy , Lyon Alice , Anderson-Nelson Susan , Jampol Lee M. , Weinberg David V. , Muñana Annie , Rozenbajgier Zuzanna , Orth David , Cohen Jack , MacCumber Matthew , MacCumber Matthew , Figliulo Celeste , Porcz Liz , Folk James , Boldt H. Culver , Russell Stephen R. , Ivins Rachel , Hinz Connie J. , Barr Charles C. , Bloom Steve , Jaegers Ken , Kritchman Brian , Whittington Greg , Heier Jeffrey , Frederick Albert R. , Morley Michael G. , Topping Trexler , Davis Heather L. , Bressler Susan B. , Bressler Neil M. , Doll Warren , Trese Michael , Capone Antonio , Garretson Bruce R. , Hassan Tarek S. , Ruby Alan J. , Osentoski Tammy , McCannel Colin A. , Ruszczyk Margaret J. , Grand Gilbert , Blinder Kevin , Holekamp Nancy M. , Joseph Daniel P. , Shah Gaurav , Nobel Ginny S. , Antoszyk Andrew N. , Browning David J. , Stallings Alison H , Singerman Lawrence J. , Miller David , Novak Michael , Pendergast Scott , Zegarra Hernando , Schura Stephanie A. , Smith-Brewer Sheila , Davidorf Frederick H. , Chambers Robert , Chorich Louis , Salerno Jill , Dreyer Richard F. , Ma Colin , Kopfer Marcia R. , Klein Michael L. , Wilson David J. , Nolte Susan K. , Grunwald Juan E. , Brucker Alexander J. , Dunaief Josh , Fine Stuart L. , Maguire Albert M. , Stoltz Robert A. , McRay Monique N. , Fish Gary Edd , Anand Rajiv , Spencer Rand , Arnwine Jean , Chandra Suresh R. , Altaweel Michael , Blodi Barbara , Gottlieb Justin , Ip Michael , Nork T. Michael , Perry-Raymond Jennie , Fine Stuart L. , Maguire Maureen G. , Brightwell-Arnold Mary , Harkins Sandra , Peskin Ellen , Ying Gui-Shuang , Kurinij Natalie 
Published: April 2010

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 × 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 × 10
−7
;
CETP
,
P
= 7.4 × 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 × 10
−3
) and
ABCA1
(
P
= 5.6 × 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.