AUTHOR=Zhou Xueping , Zhang Jipeng , Ding Ying , Huang Heng , Li Yanming , Chen Wei 

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

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1075824

DOI=10.3389/fgene.2023.1075824

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>via</italic> 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.</p><p><bold>Results:</bold> Several previously identified late-stage age-related macular degeneration susceptibility genes, for example, <italic>BTBD16</italic>, <italic>C3</italic>, <italic>CFH</italic>, <italic>CFHR3</italic>, <italic>HTARA1</italic>, are confirmed. Novel genes <italic>DENND1B</italic>, <italic>PLK5</italic>, <italic>ARHGAP45</italic>, and <italic>BAG6</italic> 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.</p><p><bold>Conclusion:</bold> 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.</p>