Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

Area of Science:

• Ophthalmology and Genetics
• Human Genetics

Background:

• Refractive error, a complex eye condition, is influenced by genetic and environmental factors.
• Genome-wide association studies (GWAS) have identified common genetic risk factors, but a significant portion of heritability remains unexplained.
• Rare genetic variants (minor allele frequency [MAF] ≤ 0.01) may contribute to the missing heritability of refractive error.

Purpose of the Study:

• To investigate the association between rare genetic variants and refractive error using gene-based association tests.
• To identify novel genes contributing to the genetic basis of refractive error.

Main Methods:

• Analysis of exome array data from the Consortium for Refractive Error and Myopia (CREAM) dataset.
• Involved over 27,000 subjects from five Indo-European and Eastern Asian cohorts.
• Performed multiple gene-based association tests on mean spherical equivalent (SER) with rare variants.

Main Results:

• Identified 129 unique genes significantly associated with refractive error.
• Replication of findings across multiple cohorts.
• Highlighted novel candidate genes including PDCD6IP, PER3, and P4HTM.

Conclusions:

• Rare variants play a role in the genetic architecture of refractive error.
• The identified genes offer new targets for understanding refractive error development.
• Further functional studies and validation are warranted to elucidate gene function and therapeutic potential.