Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).
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.
Neale
Benjamin M
BM
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Fagerness
Jesen
J
Reynolds
Robyn
R
Sobrin
Lucia
L
Parker
Margaret
M
Raychaudhuri
Soumya
S
Tan
Perciliz L
PL
Oh
Edwin C
EC
Merriam
Joanna E
JE
Souied
Eric
E
Bernstein
Paul S
PS
Li
Binxing
B
Frederick
Jeanne M
JM
Zhang
Kang
K
Brantley
Milam A
MA
Lee
Aaron Y
AY
Zack
Donald J
DJ
Campochiaro
Betsy
B
Campochiaro
Peter
P
Ripke
Stephan
S
Smith
R Theodore
RT
Barile
Gaetano R
GR
Katsanis
Nicholas
N
Allikmets
Rando
R
Daly
Mark J
MJ
Seddon
Johanna M
JM
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
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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