Journal article

Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder

Roberto Bonelli, Victoria E Jackson, Aravind Prasad, Jacob E Munro, Samaneh Farashi, Tjebo FC Heeren, Nikolas Pontikos, Lea Scheppke, Martin Friedlander, Catherine A Egan, Rando Allikmets, Brendan RE Ansell, Melanie Bahlo



Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p < 5 × 10-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR = 3.9 × 10-47) and glycine depletion (FDR = 0.006) as well as alanine abundance (FDR = 0.009). Polygenic risk..

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University of Melbourne Researchers


Awarded by Australian National Health and Medical Research Council (NHMRC) Fellowship

Awarded by NHMRC Early Career Fellowship

Funding Acknowledgements

The authors would like to thank the Lowy Medical Research Institute for funding to conduct this study. We also thank Professor Nick Martin, Queensland Institute of Medical Research (QIMR), for access to the unpublished Twins Study data for controls; and Professor Stuart McGregor (QIMR) for a discussion on Mendelian Randomisation studies in cancer risk and MacTel. We thank Dr. Rinki Ratnapriya and Professor Anand Swaroop (NEI) for generously providing access to genotype data to allow targeted retinal eQTL analysis. We acknowledge the use of UK Biobank data (project application 36610) and access to the metabolomic PRS (courtesy of Dr. Claudia Langenberg, Medical Research Council, Cambridge, UK). M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Fellowship (GNT 1102971). B.R.E.A. was supported by an NHMRC Early Career Fellowship (GNT 1157776). R.B. was supported by a Melbourne International Research Scholarship and the John and Patricia Farrant Foundation. This work was also supported by the Victorian Government's Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Finally, the authors wish to thank the MacTel patients and their families for their involvement in this study.