Predicting late-stage age-related macular degeneration by integrating marginally weak SNPs in GWA studies

Abstract

Introduction: Age-related macular degeneration (AMD) is a progressive neurodegenerative disease and the leading cause of blindness in developed countries. Current genome-wide association studies (GWAS) for late-stage age-related macular degeneration are mainly single-marker-based approaches, which investigate one Single-Nucleotide Polymorphism (SNP) at a time and postpone the integration of inter-marker Linkage-disequilibrium (LD) information in the downstream fine mappings. Recent studies showed that directly incorporating inter-marker connection/correlation into variants detection can help discover novel marginally weak single-nucleotide polymorphisms, which are often missed in conventional genome-wide association studies, and can also help improve disease prediction accuracy.Methods: Single-marker analysis is performed first to detect marginally strong single-nucleotide polymorphisms. Then the whole-genome linkage-disequilibrium spectrum is explored and used to search for high-linkage-disequilibrium connected single-nucleotide polymorphism clusters for each strong single-nucleotide polymorphism detected. Marginally weak single-nucleotide polymorphisms are selected via a joint linear discriminant model with the detected single-nucleotide polymorphism clusters. Prediction is made based on the selected strong and weak single-nucleotide polymorphisms.Results: Several previously identified late-stage age-related macular degeneration susceptibility genes, for example, BTBD16, C3, CFH, CFHR3, HTARA1, are confirmed. Novel genes DENND1B, PLK5, ARHGAP45, and BAG6 are discovered as marginally weak signals. Overall prediction accuracy of 76.8% and 73.2% was achieved with and without the inclusion of the identified marginally weak signals, respectively.Conclusion: Marginally weak single-nucleotide polymorphisms, detected from integrating inter-marker linkage-disequilibrium information, may have strong predictive effects on age-related macular degeneration. Detecting and integrating such marginally weak signals can help with a better understanding of the underlying disease-development mechanisms for age-related macular degeneration and more accurate prognostics.

The Complement System as a Therapeutic Target in Retinal Disease

“…The CFH gene is found on chromosome 1q31, and its protein product is a negative regulator of the complement cascade, as described above [ 50 ]. Genome-wide association studies have identified that polymorphisms in genes encoding complement factor B, complement factor H-related protein 3, complement factor I, C2, and C3 are associated with AMD in varying capacities [ 53 , 54 , 55 ].…”

The Role of Inflammation in Age-Related Macular Degeneration—Therapeutic Landscapes in Geographic Atrophy

“…In the aging retina, there is building evidence of para-inflammation in the retina over time [ 10 ]. There are many genetic factors, such as, C3 , CFH and CFHR3 , that increase the risk of late-stage AMD reported by genome-wide association studies (GWAS) [ 11 , 12 ]. Environmental risk factors, such as smoking, diet and exercise, also result in oxidative stress on RPE cells [ 13 ].…”

Transcriptomic Gene Network Profiling and Weak Signal Detection for Prediction of Ovarian Cancer Occurrence, Survival, and Severity by Integrating Bulk and Single-cell RNAseq Data

“…Through a series of work, Li et al [19][20][21][22][23] have shown that in cancer-genomic studies, some genes, even though having weak marginal differential effects (DE), may still exude strong prediction effects on disease outcomes though regulating other strong DE genes. These weak DE genes (or weak genes), together with their coregulated strong genes and the coregulations between them, form predictive gene networks (PDN).…”