Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.
OBJECTIVE
To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.


METHODS
Sibling correlation study and genome-wide association study (GWAS).


METHODS
For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.


METHODS
Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.


METHODS
Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.


RESULTS
The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).


CONCLUSIONS
Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
Lucia
L
Sobrin
Stephan
S
Ripke
Yi
Y
Yu
Jesen
J
Fagerness
Tushar R
TR
Bhangale
Perciliz L
PL
Tan
Eric H
EH
Souied
Gabriëlle H S
GH
Buitendijk
Joanna E
JE
Merriam
Andrea J
AJ
Richardson
Soumya
S
Raychaudhuri
Robyn
R
Reynolds
Kimberly A
KA
Chin
Aaron Y
AY
Lee
Nicolas
N
Leveziel
Donald J
DJ
Zack
Peter
P
Campochiaro
R Theodore
RT
Smith
Gaetano R
GR
Barile
Ruth E
RE
Hogg
Usha
U
Chakravarthy
Timothy W
TW
Behrens
André G
AG
Uitterlinden
Cornelia M
CM
van Duijn
Johannes R
JR
Vingerling
Milam A
MA
Brantley
Paul N
PN
Baird
Caroline C W
CC
Klaver
Rando
R
Allikmets
Nicholas
N
Katsanis
Robert R
RR
Graham
John P A
JP
Ioannidis
Mark J
MJ
Daly
Johanna M
JM
Seddon
D020256:Choroidal Neovascularization / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D057092:Geographic Atrophy / Q000235:genetics*; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*; D035781:Siblings
C514392:ARMS2 protein, human; D011506:Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases