Genome-wide association study and identification of systemic comorbidities in development of age-related macular degeneration in a hospital-based cohort of Han Chinese

Abstract

Background: Age-related macular degeneration (AMD) is the main cause of severe vision loss in elderly populations of the developed world with limited therapeutic medications available. It is a multifactorial disease with a strong genetic susceptibility which exhibits the differential genetic landscapes among different ethnic groups.Methods: To investigate the Han Chinese-specific genetic variants for AMD development and progression, we have presented a genome-wide association study (GWAS) on 339 AMD cases and 3,390 controls of a Han Chinese population recruited from the Taiwan Precision Medicine Initiative (TPMI).Results: In this study, we have identified several single nucleotide polymorphisms (SNPs) significantly associated with AMD, including rs10490924, rs3750848, and rs3750846 in the ARMS2 gene, and rs3793917, rs11200638, and rs2284665 in the HTRA1 gene, in which rs10490924 was highly linked to the other variants based upon linkage disequilibrium analysis. Moreover, certain systemic comorbidities, including chronic respiratory diseases and cerebrovascular diseases, were also confirmed to be independently associated with AMD. Stratified analysis revealed that both non-exudative and exudative AMD were significantly correlated with these risk factors. We also found that homozygous alternate alleles of rs10490924 could lead to an increased risk of AMD incidence compared to homozygous references or heterozygous alleles in the cohorts of chronic respiratory disease, cerebrovascular disease, hypertension, and hyperlipidemia. Ultimately, we established the SNP models for AMD risk prediction and found that rs10490924 combined with the other AMD-associated SNPs identified from GWAS improved the prediction model performance.Conclusion: These results suggest that genetic variants combined with the comorbidities could effectively identify any potential individuals at a high risk of AMD, thus allowing for both early prevention and treatment.

Identification of Genetic Variants for Risk Prediction and Early Diagnosis of Age-Related Macular Degeneration in the Taiwanese Population

“…Both models were suitable for predicting dry AMD (AUC: 0.654 for model 1 and 0.646 for model 2) and wet AMD (AUC: 0.692 for model 1 and 0.659 for model 2). Previously reported AUCs for genetic models for AMD prediction in Taiwan were 0.651-0.693 [21], which are similar to those in our study. A recently constructed AMD PRS for individuals of European ancestry showed an AUC of 0.60 (95% CI: 0.54-0.65) for East Asians [18].…”

“…In our cohort, we did not identify any SNPs in CFH that reached GWAS significance ( p < 5 × 10 −8 ), despite the reported association between this locus and AMD in East Asian populations [ 19 ]. Consistent with these findings, variants in CFH did not reach GWAS significance for AMD in another Taiwanese population [ 21 ]. This gene may play a less important role in AMD development in the Taiwanese population than in other populations.…”

“…A cluster of SNPs with high LD surrounding the PLEKHA1 , LOC105378525 , ARMS2 , and HTRA1 loci on chromosome 10q26 was identified in the GWAS. The rs11200630 was the most significant SNP in LD after rs59616332 and showed high LD with rs10490924 ( r 2 = 0.941), which is associated with an elevated risk of AMD in other Taiwanese populations [ 21 ]. The rs11200630 is a non-coding SNP and was related to an elevated AMD risk in the present study; this SNP was located near ARMS2 and HTRA1 , which are strong genetic risk factors for AMD according to a GWAS of European and East Asian populations [ 16 , 18 , 19 , 22 , 23 ].…”