Novel loci for ocular axial length identified through extreme-phenotype genome-wide association study in Chinese populations.

Purpose: To investigate genetic loci associated with ocular axial length (AL) in the Chinese population.

Methods: A genome-wide association study meta-analysis was conducted in totalling 2644 Chinese individuals from 3 cohorts: the Guangzhou cohort (GZ, 537 high myopes and 151 hyperopes), Wenzhou cohort (334 high myopes and 6 hyperopes) and Guangzhou Twin Eye Study (1051 participants with normally distributed AL). Functional mapping was performed to annotate the significant signals, possible tissues and cell types by integrating available multiomics data. Logistic regression models using AL-associated SNPs were constructed to predict three AL status in GZ.

Results: Two novel loci (1q25.2 and 7p22.2 ) showed genome-wide significant associations with AL, together explaining 29.63% of AL variance in GZ. The two lead SNPs improved the prediction accuracy for AL status, especially for hyperopes. The frequencies of AL decreasing (less myopic) alleles of the two SNPs were lowest in East Asians as compared with other populations (rs17370084: =0.03, =0.24, =0.05; rs73046501: =0.06, =0.07, =0.20), which was in line with the global distribution of myopia. The cerebral cortex and gamma-aminobutyric acidergic interneurons showed possible functional involvement in myopia development, and the galactose metabolic pathways were significantly enriched.

Conclusion: Our study identified two population-specific novel loci for AL, expanding our understanding of the genetic basis of AL and providing evidence for a role of the nervous system and glucose metabolism in myopia pathogenesis.