Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 WashingtonStreet, No. 450, Boston, MA 02111, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2011; 20(18):3699-709. DOI: 10.1093/hmg/ddr270
Source: PubMed


Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

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    • "(APOE, LIPC, CETP), components of the extracellular collagen matrix (TIMP3, COL8A1, COL10A1), and proteins promoting angiogenesis (VEGFA, TGFBR1) (Yu et al. 2011; Fritsche et al. 2013). The most comprehensive genomewide association study performed thus far involved 18 international research groups, and included .17,000 "
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    ABSTRACT: Age-related macular degeneration (AMD) is a complex disease caused by a combination of genetic and environmental factors. Genome-wide association studies have identified several common genetic variants associated with AMD, which together account for 15%-65% of the heritability of AMD. Multiple hypotheses to clarify the unexplained portion of genetic variance have been proposed, such as gene-gene interactions, gene-environment interactions, structural variations, epigenetics, and rare variants. Several studies support a role for rare variants with large effect sizes in the pathogenesis of AMD. In this work, we review the methods that can be used to detect rare variants in common diseases, as well as the recent progress that has been made in the identification of rare variants in AMD. In addition, the relevance of these rare variants for diagnosis, prognosis, and treatment of AMD is highlighted.
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    • "The studies performed in American twins revealed that the heritability of AMD, that is, the relative contribution of genetic and nongenetic factors to the phenotype, is estimated at a relatively high value of between 45% and 70% [30]. It was also estimated that currently identified loci account for approximately 55% of AMD heritability [31]. Recently, the international scientific group performed the multicenter meta-analysis involving more than 17 000 cases of AMD and 60 000 control patients defining an association between AMD and genetic variants in a total of 19 chromosomal regions [32]. "
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    ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch's membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.
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    • "Other studies were unable to confirm these associations (Pang et al., 2000; Schultz et al., 2003) that are attenuated or absent when adjusted for age (Adams et al., 2012). Many other loci of modest effect have also been identified and replicated in genome-wide association studies (GWAS) including CETP, LIPC, TIMP3, VEGFA, TNFRSF10A, COL10A1, COL8A1/ FILIP1L, SLC16A8, IER3/DDR1, TGFBR1, RAD51B, ADAMTS9/MIR548A2, and B3GALTL (Chen et al., 2010; Fritsche et al., 2013; Yu et al., 2011). "

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