Background: Macular Telangiectasia Type 2 (MacTel) is a rare, degenerative disorder of the macula, characterised by gradual loss of central vision. Previous genome-wide association studies (GWAS) have identified several genetic risk loci for MacTel, with a prominent role for serine and glycine metabolism. Although GWAS has become common practice for disorders such as MacTel, the role of the mitochondrial genome is often neglected. GWAS of the mitochondrial genome (mitoGWAS), have the potential to reveal hidden contributions of mitochondrial variants and elucidate further etiological mechanisms.
Method & Results: We conducted the first mitoGWAS using the Infimum Global Screening Array (GSA) on a cohort of 1,412 MacTel cases and 1,480 controls. The analysis was limited to individuals genetically similar to European 1000 genome samples and corrected for ancestry and relatedness from the nuclear genome. We identified a significantly associated mitochondrial haplotype with MacTel (Bonferroni Adjusted P-Value: 0.025, OR: 2.8, 95% CI: [1.6, 4.8]). This haplotype, characterized by three significant mitochondrial SNPs with low frequency (MAF: 0.019) among Europeans, appears to be a more recently arisen subgroup of the major Haplogroup N. A subset of individuals with the enriched mitochondrial haplotype underwent whole-genome sequencing to identify and assess the causality of rare mitochondrial variants. This study identifies the first mitochondrial risk factor for MacTel, a disease for which mitochondrial dysregulation has been previously hypothesised to play a role.