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Primary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup–disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in  SIX1–SIX6  locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in  SIX6  associated with VCDR ( P  meta  = 7.74 × 10 −7 ,  n  = 11 473) and POAG ( P  meta  = 6.09 × 10 −3 ,  n  = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in  SIX6  associated with VCDR ( P  = 5.09 × 10 −3 ,  n  = 1208). These two findings point to  SIX6  as the responsible gene for the previously reported association signal. Functional characterization of  SIX6  in zebrafish revealed that knockdown of  six6b  led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up-regulation of  cdkn2b , a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both  six6b  and  cdkn2b  play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of  six6b  in early eye development, and open new insights into the genetic architecture of POAG.

human molecular genetics

Exome sequencing and functional analyses suggest that  SIX6  is a gene involved in an altered proliferation–differentiation balance early in life and optic nerve degeneration at old age