Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups

Abstract:
Primary open-angle glaucoma (POAG) is a complex eye disease characterized by progressive loss of optic nerve function that if untreated ultimately leads to irreversible blindness. To date, the biological mechanisms causing POAG are still unclear.  Here, we aim to explore the biology underlying the potential vascular connection with POAG. The Global Biobank Meta-Initiative (GBMI), a collaboration of 20 global biobanks, provides an exceptional resource to examine potential shared vascular POAG biology, with 46,325 patients from six ancestries (N=1,478,037). A total of 103 genome-wide significantly associated loci were identified, 14 of which were novel (i.e. CATSPERB, KALRN, and HMGXB3). To add biological context to these variant-trait associations, we performed gene prioritization analysis and transcriptome-wide association studies (TWAS) using 23 tissues potentially relevant to ocular conditions, implicating genes related to vascular-related functions, blood vessels, angiogenesis, or cancer. Gene enrichment analysis showed that genes involved in morphology and development of blood vessels and angiogenesis pathways were significantly overrepresented in our loci. Gender specific association analysis identified an African male-specific variant in the gene CELSR2, which is involved in the regulation levels of low-density lipoprotein cholesterol in blood and in tumorigenesis. Further we performed extensive statistical validation analysis of genes in the SIX6 and CDKN2B-AS1 loci, previously implicated in POAG, cardiovascular diseases, and cancers across multiple ancestries. The results confirmed that the TWAS signals in these loci can be attributed to the sentinel rs33912345 missense variant in the SIX6 gene and variants linked to the CDKN2B-AS1 gene. We also found evidence of significant interaction between the rs33912345 and causal variants in chr9p21.3, with concomitant effect on expression of the genes CDKN2A and CDKN2B. We confirmed shared biology between cardiovascular diseases, cancer, and POAG by performing meta-analysis cis model TWAS-PheWAS across the whole phenome in BioVU and UKbiobank data (n=456,423). In summary, our findings enforce the contribution of genes involved in vascular and proliferation mechanisms that convey toward a possible involvement of primary cilia in the POAG pathogenesis.