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Page 241 Ratnapriya. J Transl Genet Genom 2022;6:240-256 https://dx.doi.org/10.20517/jtgg.2021.54

in the post-genome era. Genome-wide association studies (GWASs) have been instrumental in bringing us
closer to the goal of understanding the genetic basis of complex diseases faster than ever before. GWAS have
been conducted in ~3000 diseases and quantitative traits that have led to the identification of 71,673 trait-
[1]
associated single nucleotide polymorphisms (SNPs) from 5687 studies . These studies have provided the
following insights into the genetic architecture of complex diseases; (1) complex traits are highly polygenic;
(2) multiple independent association signals at each locus are not uncommon; (3) effect sizes of individual
associated variants are small; and (4) the majority (~93%) of disease- and trait-associated variants lie within
the noncoding sequence.

GWASs have undoubtedly established the critical role of common variants in complex diseases. However,
these findings did not immediately reveal the causal variant, gene or biological mechanisms underlying the
observed genetic association. Thus, it is time to envision the post-GWAS phase of human genetics that
focuses on accelerating progress in moving genetic association to functional interpretation. Translating the
genetic findings to meaningful biology warrants having a comprehensive picture of the causal variants and
genes, disease-relevant cells, tissues and organ through which genes act, and the biological pathways and
mechanisms driving the disease. In the past few years, functional studies to connect GWAS to biology have
been gaining momentum, which could be largely attributed to our enhanced ability to generate and
[2]
integrate genomic data at the genome, transcriptome and epigenome level . Gaining a molecular
understanding of genetic findings warrants the integration of genetic results with other biological data types
from disease-relevant tissues and cell types and careful functional studies that ought to be tailored for
different diseases.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss resulting from the
death of light-sensing photoreceptors, primarily in the central region of the retina called the macula. It is a
complex multifactorial disease caused by the cumulative impact of genetic predisposition, environmental
[3-5]
stress and advanced aging . AMD afflicts almost 10 million individuals in the United States alone .
[6]
Fundus features such as large, soft drusen and pigmentary abnormalities are associated with an increased
[7]
risk of AMD progression . It is a progressive disease with early, intermediate and late stages of disease.
Early/intermediate AMD is the most common and least severe form, characterized by pigmentary
abnormalities in the macula and accumulation of extracellular aggregates of proteins, lipids and cellular
components (called drusen). AMD in the advanced stage is subdivided into dry (geographic atrophy, or
GA) and wet (choroidal neovascularization, or CNV) . In the United States, over 1.75 million people have
[8]
advanced stage of AMD, and 7.3 million people are affected with intermediate stage and are at the risk of
developing advanced AMD. Patients with neovascular AMD respond well to treatment with anti-vascular
endothelial growth factor (VEGF) agents, but those diagnosed with the dry form of the disease
(approximately 85% of AMD cases) have no approved treatment options available to them . Detecting the
[9]
disease early can provide a window of opportunity to avoid or delay the burden of vision loss on both the
patient and their families. The earlier that AMD is detected, the earlier steps can be taken to help slow its
progression and save sight through treatment and/or lifestyle modifications. However, there is a paucity of
studies on the early and intermediate stages of AMD, and as a result, there are no reliable biomarkers for
predicting the disease progression to either GA or CNV. In the absence of treatment, antioxidant vitamins
and mineral supplements remain the best option for slowing the progression of the disease in individuals at
a high risk of developing AMD .
[10]

GENETICS STUDIES IN AMD
Remarkable progress has been made in delineating the genetic basis of AMD. Familial aggregation, twin
studies, and segregation analyses indicated substantial genetic contributions to AMD pathogenesis that