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Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPACD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.

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Acknowledgements

This work was conducted using the UK Biobank Resource (application number 25331), the Genetic Epidemiology Research on Aging (GERA) cohort (dbGaP, study accession: phs000674.v3.p3), and publicly available data from the International AMD Genomics Consortium (IAMDGC). We want to acknowledge the participants and investigators of the FinnGen study. We thank Scott Wood, Xiaping Lin, John Pearson, and Scott Gordon from QIMR Berghofer for their support. The GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; Schaefer and Risch, PIs) awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Northern California Community Benefit Programs. The RPGEH and the Resource for Genetic Epidemiology Research in Adult Health and Aging are described in the following publication, Schaefer et al., The Kaiser Permanente Research Program on Genes, Environment, and Health: Development of a Research Resource in a Multi-Ethnic Health Plan with Electronic Medical Records, in preparation, 2013.

Funding

SMG and AWH are supported by Australian National Health and Medical Research Council (NHMRC) Fellowships. We acknowledge funding from NHMRC grants 1116360, 1150144, and 1123248.

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Han, X., Gharahkhani, P., Mitchell, P. et al. Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration. J Hum Genet 65, 657–665 (2020). https://doi.org/10.1038/s10038-020-0750-x

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