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Genome-wide analyses identify common variants associated with macular telangiectasia type 2

Abstract

Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10−8) were identified at three independent loci (rs73171800 at 5q14.3, P = 7.74 × 10−17; rs715 at 2q34, P = 9.97 × 10−14; rs477992 at 1p12, P = 2.60 × 10−12) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1,134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences in blood serum levels of glycine (P = 4.04 × 10−6) and serine (P = 2.48 × 10−4) between MacTel cases and controls.

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Figure 1: Genome-wide plot of association.
Figure 2: Regional plots of association.
Figure 3: Pathway analysis.
Figure 4: Regional plots of association.

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Acknowledgements

We acknowledge The Genomics Core Facility at the University of Utah School of Medicine for processing the Illumina Human Omni5 Exome BeadChips used in this study. This study was supported by the Lowy Medical Research Institute (La Jolla, California). We thank and acknowledge all of the participants of the MacTel Project (patients and controls) who have given their time, provided biological samples and undergone extensive testing for this study. The Age-Related Eye Disease Study (AREDS) control data set used for the discovery GWAS analyses described in this manuscript were obtained from the database at http://www.ncbi.nlm.nih.gov/ through database of Genotypes and Phenotypes (dbGaP) accession phs000429.v1.p1. Funding support for AREDS was provided by the National Eye Institute (N01-EY-0-2127). We would like to thank the AREDS participants and the AREDS Research Group for their valuable contribution to this research. We thank E. Agron for providing the AREDS diabetes summary statistics. We thank and acknowledge the staff and participants of the SABRE study who provided metabolomics data. Funding for the control group from the SABRE study was provided by the Wellcome Trust (WT082464), the British Heart Foundation (SP/07/001/23603) and Diabetes UK (13/0004774). Funding support for the control cohort at Columbia University was, in part, provided by NIH/NEI grant EY013435. This research was supported in part by the National Institute for Health Research (NIHR) Moorfields Biomedical Research Centre (London, UK). The views expressed are those of the authors and not necessarily those of the NIHR. This work was supported by Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. M.B. is supported by an NHMRC Senior Research Fellowship (APP1002098) and an NHMRC Program Grant (APP1054618). Finally, we thank S. Freytag, T. Speed and G.K. Smyth for useful discussions with respect to statistical analyses and K. Khan for contributing serum samples for the metabolomics study.

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Contributions

T.S.S. designed the study, performed the analyses, interpreted the results, reviewed the literature on MacTel and wrote the manuscript. A.Q. performed the prediction modeling and other statistical analyses and helped write the manuscript. C.C. maintained the MacTel genetics database, including DNA isolation and preparation for genotyping from all MacTel subjects and controls and data organization. J.Z. performed TaqMan genotyping of the replication cohort and some data analysis. N.M. performed the GWAS SNP chip genotyping and helped write the manuscript. L.B. performed the GWAS SNP chip genotyping. L.S. organized patient databases and helped write the manuscript. R.B. performed the heritability and eQTL analyses and assisted with the metabolomics analysis. L.A.Y. obtained genetic material from the MacTel Project samples. M. Friedlander managed the study, helped interpret the results and helped write the manuscript. MacTel Project consortium members included clinicians and scientists who phenotyped the cohort of patients with MacTel and replication controls used in the study. C.A.E. and M. Fruttiger led the metabolomics study and interpreted the metabolomics data. M.L. led the genotyping group, helped design the study, interpreted the results and helped write the manuscript. R.A. led the genetics group, including obtaining genetic material from MacTel Project samples and the Columbia University controls and obtaining replication genotyping data, helped design the study, interpreted the results and helped write the manuscript. M.B. led the statistical analysis group, designed the study and helped write the manuscript.

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Correspondence to Melanie Bahlo.

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The authors declare no competing financial interests.

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A list of members and affiliations appears in Supplementary Table 1.

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Supplementary Text and Figures

Supplementary Figures 1–27 and Supplementary Tables 1, 2 and 4–9 (PDF 3698 kb)

Supplementary Fig. 28

B-allele frequency and log R ratio plots, and TaqMan genotype intensity assay plots, for the SNPs highlighted in Table 2 and the three SNPs determined to be false positives. (PDF 3633 kb)

Supplementary Table 3

All 647 SNPs that were either genome-wide significant (P < 5 × 10–8) or otherwise suggestive (P < 1 × 10–5) associations for MacTel in our discovery stage. (XLSX 134 kb)

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Scerri, T., Quaglieri, A., Cai, C. et al. Genome-wide analyses identify common variants associated with macular telangiectasia type 2. Nat Genet 49, 559–567 (2017). https://doi.org/10.1038/ng.3799

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