Genetic Association Analysis of Drusen Progression.
OBJECTIVE
Age-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis.


METHODS
Exome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure.


RESULTS
We observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (ρ = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02).


CONCLUSIONS
In this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk.
Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States.
Joshua D
JD
Hoffman
Diagnostic Image Analysis Group, Radboud University Medical Center, Nijmegen, The Netherlands.
Mark J J P
MJ
van Grinsven
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
Chun
C
Li
Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, Tennessee, United States.
Milam
M
Brantley
Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States.
Josephine
J
McGrath
Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, Tennessee, United States.
Anita
A
Agarwal
John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
William K
WK
Scott
Ophthalmology, Bascom Palmer Eye Institute, Retina Center of Naples, Naples, Florida, United States.
Stephen G
SG
Schwartz
Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, Florida, United States.
Jaclyn
J
Kovach
John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States.
Margaret
M
Pericak-Vance
Diagnostic Image Analysis Group, Radboud University Medical Center, Nijmegen, The Netherlands.
Clara I
CI
Sanchez
Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States 8Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States.
Jonathan L
JL
Haines
D000368:Aged; D018450:Disease Progression; D005260:Female; D005654:Fundus Oculi; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015593:Retinal Drusen / Q000175:diagnosis / Q000235:genetics*; D012307:Risk Factors