By pairing large cross-ancestry GWAS meta-analysis with transcriptomic, proteomic, and cross-trait genetic evidence, the study broadens the genetic map of cataract in both European and East Asian populations and puts forward a set of genetically supported candidate genes and proteins. These findings offer a framework for moving from locus discovery toward mechanistically grounded target prioritisation, though the authors note that ocular tissue-specific QTL data and experimental follow-up will be needed to confirm the biological relevance of these candidates for preventing or slowing cataract progression.
Background
Cataract remains one of the world's leading causes of visual impairment and blindness. While prior genome-wide association studies (GWAS) have mapped a number of cataract risk loci, most of this evidence has not yet been translated into an integrated, multi-omics picture of the disease, and there has been limited progress connecting these signals to biologically plausible targets that could help prevent or slow age-related cataract.
Findings
The authors carried out a senile cataract GWAS in the All of Us cohort, then combined it with existing data into ancestry-specific meta-analyses covering over 1.1 million European-ancestry participants and more than half a million East Asian-ancestry participants. This yielded 78 independent risk loci in Europeans (8 not previously reported) and 4 in East Asians (3 not previously reported). Layering in cis-eQTL Mendelian randomisation (MR) against the meta-GWAS prioritised 16 candidate genes, with MTMR3 and NT5DC2 additionally supported by colocalisation. A parallel proteome-wide cis-pQTL MR scan nominated 32 candidate proteins in Europeans, narrowed by colocalisation to EFNA1 and RALY, while in East Asians APOE and ALDH2 emerged as the leading candidates. The authors also found colocalised pleiotropic signals linking cataract to myopia, hypertension, and type 2 diabetes, pointing to genes such as TCF7L2, BMP4, CDKAL1, and PAX4.