Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder.
Roberto BonelliVictoria E JacksonAravind PrasadJacob E MunroSamaneh FarashiTjebo F C HeerenNikolas PontikosLea ScheppkeMartin Friedlandernull nullCatherine A EganRando AllikmetsBrendan Robert E AnsellMelanie BahloPublished in: Communications biology (2021)
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 scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p = 0.009). This represents the largest genetic study on MacTel to date and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.
Keyphrases
- genome wide
- optical coherence tomography
- diabetic retinopathy
- dna methylation
- genome wide association study
- end stage renal disease
- optic nerve
- ejection fraction
- newly diagnosed
- gene expression
- healthcare
- peritoneal dialysis
- public health
- mental health
- patient reported outcomes
- oxidative stress
- single cell
- endothelial cells
- social media
- rna seq
- drug induced
- stress induced
- data analysis
- bioinformatics analysis