Whole-Genome Association Study of Age-Related Macular Degeneration in the Israeli Population

Abstract

Purpose : The elderly Israeli population is composed of a few major ethnic groups (Ashkenazi Jewish, Sephardic Jewish, and Arab populations). Each population bares their own susceptibility to genetic disorders. We wished to analyze Israeli patients with age-related macular degeneration (AMD) from variable ethnic origins to discover possible risk factors for AMD on a genome wide level.

Methods : DNA was collected from AMD patients (n=403) and controls (n=256) from variable ethnic backgrounds in a single tertiary center. Demographics, clinical, and imaging parameters were retrospectively collected. Genotyping was performed via the International AMD Genomics Consortium (IAMDGC) exome chip platform, and bioinformatics was performed with PLINK and EPACTS. Data was imputed to around 12 million variants, but around 30% of variants were excluded after quality control (QC). A genome wide association study (GWAS) was performed using informative principle components, age, and gender as covariates. Variants with minor allele frequencies<0.01 were excluded. Variants were clumped via P-value and linkage was taken into account. Variants of interest were looked at as compared with the IAMDGC results and genetics from the Ashkenazi Genome Consortium to exclude ethnic bias. Significant P-value threshold for analysis was set at 1x10^-3.

Results : A GWAS in the total Israeli population between AMD patients and controls indicated verification of significant variants previously identified by the IAMDGC in ARMS2/HTRA1 (P<2x10^-9), CFH (P<4x10^-10), C3 (P=0.0001), C20orf85 (P=0.0004), SLC16A8 (P=0.0007) and SYN3/TIMP3 (P=0.0009). A copy number variation in ARMS2/HTRA1 is possibly higher in Ashkenazi AMD patients (P=0.001, homozygote n=42/215 cases, n=6/113 controls). Comparison between the Ashkenazi and Arab (n=36 cases, 30 controls) populations shows the top ranking variant known to be associated with AMD in the Arab population is in the ARMS2/HTRA1 (P=0.0003), while the top ranking variant in the Ashkenazi population is CFH gene (P=5x10-9).

Conclusions : We report the first GWAS on the Israeli population of AMD patients. Variants already associated with AMD in other populations were validated in the Israeli population, albeit with differential significance levels between subpopulations.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.