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Rinki Ratna Priya, Samuel Perez, Mousumi Mutsuddi, Vijender Chaitankar, Mohammad Othman, John Heckenlively, Kari Branham, Anand Swaroop; Whole exome sequencing reveals novel pathways implicated in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):789.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is the most common cause of visual impairment in the elderly. Genome-wide association studies have identified 19 common susceptibility loci, which explain up to half of the AMD heritability. More recently, targeted sequencing has revealed four high-risk, rare coding variants at known AMD loci. To further investigate the role of rare variants in AMD pathogenesis, we undertook whole exome sequencing (WES) of 19 AMD families.
Exome of 69 samples from 19 families were captured using Agilent SureSelect Human All Exon kit, and sequencing data was generated on Illumina GAIIx. Reads were aligned to the human reference genome (NCBI build 37.3, hg19) using Burrows-Wheeler Aligner. Variants were called using GATK, and annotations were performed using ANNOVAR. Impact of variants was predicted using PolyPhen2, SIFT, MutationTaster, LRT and Mutation Accessor. Gene enrichment analysis was performed using database for annotation, visualization and integrated discovery (DAVID).
A total of 343 candidates were identified based on minor allele frequency (MAF ≤ 0.05%) and segregation within the family. The identified variants include four rare variants in known AMD genes and five novel genes with rare segregating variants in more than one family. This number was further reduced to 120 after filtering the variants that were predicted to be non-pathogenic by three or more prediction programs. Subjecting this list to DAVID revealed genes in extracellular matrix (ECM), transmembrane transporter activity, voltage-gated channel activity and non-membrane organelle cytoskeletons among the top annotation clusters. Many of the candidates within these clusters were highly expressed in human fetal (Retina, RPE and Choroid), aged and AMD (Retina) transcriptome data.
We have identified several variants in novel candidate genes that may contribute to AMD. WES thus complements the ongoing AMD genetics studies using exome-chip, targeted and whole genome sequencing. Our analyses further establishes ECM pathway as an important component of AMD pathogenesis as well as highlights the importance of pathway-based investigations of complex diseases.
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