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Ratnapriya. J Transl Genet Genom 2022;6:240-256 https://dx.doi.org/10.20517/jtgg.2021.54 Page 242

encouraged researchers to identify genetic risk factors associated with AMD through candidate gene,
linkage, and association studies. Traditional linkage mapping studies in large and small families with AMD
were considerably successful in identifying the genetic loci at chromosome 1q1q31, 9p13, 10q26, and
17q25 [11-13] . At the same time, human genome sequencing and development in methods to genotype
genome-wide variants in humans led to the transition to GWAS for genetic studies in AMD. The first
GWAS using merely 50 controls and 96 cases was successful in uncovering the strong association of a
coding variant (Y402H) in complement factor H (CFH) with AMD [14-16] . Subsequent studies have identified
additional non-coding variants at CFH, in other complement genes, and at the ARMS2/HTRA1 locus
(reviewed in Ref. ). In recent years, two GWAS with a large number of cases and controls have been
[17]
performed. An international collaborative effort on the meta-analysis of AMD-GWAS from 18 centers,
involving 17,000 AMD cases and 60,000 matched controls of European and Asian ancestry, reported 19
[18]
loci . The most recent AMD-GWAS was performed by International AMD Genomics Consortium, which
surveyed genome-wide variants to evaluate 16,144 patients with advanced AMD and 17,832 controls and
identified 52 independent common and rare variants at 34 loci that exhibited an association with AMD,
accounting for more than half of genomic heritability and suggest the involvement of complement, lipid
metabolism/cholesterol transport, angiogenesis, and extracellular matrix reorganization pathways in AMD
pathology [19,20] .

Although AMD is a progressive disease, majority of the genomic studies have focused on the late-stage
disease that limits our understanding of molecular and genetic underpinnings in early and intermediate
stages. More recently, two large-scale studies have looked into the genetic basis of early and intermediate
AMD. Fritsche et al. tested the association of 34 known AMD in 6657 cases of intermediate AMD and
[19]
reported a substantial overlap of genetic determinants (24/34 known AMD risk variants) between advanced
and intermediate AMD. However, 10 risk variants showed no association with intermediate AMD despite
[19]
sufficient statistical power to detect the association . Another GWAS meta-analysis of 11 data sources,
including 14,034 early AMD and 91,214 controls, identified 10 loci with 8 overlapping with advanced AMD
[21]
loci and two novel ones . These studies emphasize the importance of large-scale population-based studies
to gain insights into the genetic factors contributing to AMD progression.

Contribution of rare variants in AMD
The role of both common and rare variants contributing to the genetic architecture of complex traits has
long been recognized . It has been suggested that rare variants might contribute to the heritability in
[22]
AMD [19,23] . Targeted sequencing of candidate genes and whole-exome sequencing identified rare coding
variants in the CFH , C3 [25-27] , CFI [26,28] , C9 , CFB and COL8A1 genes within GWAS loci. Additional
[26]
[24]
[29]
[30]
studies also corroborated the findings of rare variants in complement genes [31-36] , establishing an unequivocal
role of the complement system in AMD pathology. So far, rare variants have been identified for AMD only
[19]
in a limited number of case-control studies using exome chips , exome sequencing [30,37] , and/or whole-
genome sequencing . In addition, exome sequencing in large, multiplex families also confirmed the
[36]
occurrence of rare variants in the CFH, CFI, C9 and C3 genes at multiple AMD loci [27,34,35,38-42] . However,
most of these studies were confined to looking at the rare variants within known AMD loci, and the rare
variants outside of the GWAS loci remain relatively unexplored. A recent study performed exome
sequencing of 264 individuals from 63 multiplex families with AMD and reported rare variants within eight
AMD-GWAS loci and 13 genes outside the AMD-GWAS loci . Further independent replications and
[43]
molecular investigations of rare variants are needed to understand their role in AMD pathogenesis.