Whole-exome sequencing reveals sex difference in the genetic architecture of high myopia

Background High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. To understand the sex difference in the genetic architecture of HM, which may contribute to understanding HM aetiology and help further the realisation of precision medicine for HM. Methods We performed sex-stratified exome-wide association studies (ExWAS) with n (males)=7492 and n (females)=8090, along with gene- and pathway-based tests and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to HM in a sex-specific manner. Results In our ExWAS, we identified that a male-specific gene, CHRNB1 (Z females =1.382, P females =0.083; Z males =4.029, P males =2.80×10 −05 ; P difference =0.003), was associated with higher risk scores of HM in males than in females. Rare variant burden tests showed a significant excess of rare protein-truncating variants among HM males in CHRNB1 -related pathways, including cell-cell signalling and muscle structure development. Sex-based differences in gene expression within CHRNB1 -enriched ciliary body cells were observed; specifically, increased expression of mitochondrial metabolism-related genes in males and antioxidant genes in females. Functional differences in mitochondrial metabolism were confirmed in male-derived H1 and female-derived H9 human embryonic stem cell lines, with H1 cells specifically exhibiting significant dysregulation of mitochondrial organisation and mitochondrial respiratory chain complex assembly after CHRNB1 knockdown. Conclusion Together, our study provides insight into the sex differences in the genetic architecture of HM and highlights CHRNB1 ’s role in HM pathogenesis in males.