Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-related Macular Degeneration Subtypes

Abstract

Purpose To investigate whether the two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy (GA), segregate separately in families and to identify which genetic variants are associated with these two subtypes. Design Sibling correlation study and genome-wide association study (GWAS) Participants For the sibling correlation study, we included 209 sibling pairs with advanced AMD. For the GWAS, we included 2594 participants with advanced AMD subtypes and 4134 controls. Replication cohorts included 5383 advanced AMD participants and 15,240 controls. Methods Participants had AMD grade assigned based on fundus photography and/or examination. To determine heritability of advanced AMD subtypes, we performed a sibling correlation study. For the GWAS, we conducted genome-wide genotyping and imputed 6,036,699 single nucleotide polymorphism (SNPs). We then analyzed SNPs with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. Main Outcome Measures Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. Results The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P=4.2 x 10−5) meaning that siblings of probands with CNV or GA are more likely to develop CNV or GA, respectively. In the analysis comparing participants with CNV to those with GA, we observed a statistically significant association at the ARMS2/HTRA1 locus [rs10490924, odds ratio (OR)=1.47, P=4.3 ×10−9] which was confirmed in the replication samples (OR=1.38, P=7.4 x 10−14 for combined discovery and replication analysis). Conclusions Whether a patient with AMD develops CNV vs. GA is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations which differ for advanced AMD subtypes and deserve follow-up in additional studies.

Genetic Factors for Choroidal Neovascularization Associated with High Myopia

“…The possible difference in effect of CFI compared with CFH on myopic CNV risk may be related to the fact that factor I is involved in the classic, lectin and alternative pathways, while factor H is only involved in the regulation of the alternative pathway. 55 It is interesting to note that the gene on chromosome 10, ARMS2/HTRA1, was not related to myopic CNV in this study even though this gene is more strongly associated with CNV compared with geographic atrophy in AMD 47,56 and also more strongly associated with all AMD subtypes when compared with the CFH at-risk common variant. 57 It is also noteworthy that the SNPs in the VEGF gene were not related to myopic CNV, given that VEGF rs4711751 is related to advanced dry and exudative AMD.…”

Common variant rs10033900 near the complement factor I gene is associated with age-related macular degeneration risk in Han Chinese population

“…Interestingly, we observed that the minor allele, that is, the C allele, conferred an increased risk for the development of AMD, whereas a decreased risk of such an association with AMD was reported in previous studies. 8,17,18,20 In particular, a recent Chinese study (119 exudative AMD patients and 120 controls) also reported a protective effect of rs10033900 against AMD. 22 However, we believe our result is reliable because the frequency of the C allele in our controls was 0.324, which is close to the frequency of 0.328 reported for CHB (Han Chinese in Beijing, China) from the HapMap project (http://hapmap.ncbi.nlm.nih.gov/).…”

“…14 In addition, the C allele of rs10033900 has been commonly identified as a protective allele against AMD in genetic studies. 8,14,17,18 However, there remains debate as to whether rs10033900 contributes to AMD susceptibility, due to contradicting evidence published in this journal. [18][19][20] For example, Ennis et al 20 confirmed the association between the CFI region and AMD susceptibility in a UK cohort, although rs10033900 showed no association with AMD.…”

Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations

“…Previous genome-wide association studies have identified numerous risk-associated variants within 19 susceptibility loci for AMD [6][7][8][9][10] . However, genome-wide association studies focus on common variants (minor allele frequency (MAF) 45%), which are usually located in the intronic regions of the chromosome and do not encode specific functional proteins 11,12 .…”