Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 110,260 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent participants (n = 312,825). We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP and uncovered potential therapeutic targets for glaucoma.

Intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, the leading cause of irreversible blindness worldwide. In this review, we summarize the findings of genome-wide association studies (GWASs) of IOP published in the past 10 years and prior to December 2022. Over 190 genetic loci and candidate genes associated with IOP have been uncovered through GWASs, although most of these studies were conducted in subjects of European and Asian ancestries. We also discuss how these common variants have been used to derive polygenic risk scores for predicting IOP and glaucoma, and to infer causal relationship with other traits and conditions through Mendelian randomization. Additionally, we summarize the findings from a recent large-scale exome-wide association study (ExWAS) that identified rare variants associated with IOP in 40 novel genes, six of which are drug targets for clinical treatment or are being evaluated in clinical trials. Finally, we discuss the need for future genetic studies of IOP to include individuals from understudied populations, including Latinos and Africans, in order to fully characterize the genetic architecture of IOP.

Alzheimer's disease (AD) is the most common form of late-onset neurodegenerative disease. Previous genome-wide association studies have identified numerous common genetic variants associated with AD. The contribution of rare variants to AD remains to be uncovered. AD-by-proxy, based on parental AD status, showed superior statistical power boost in recent AD studies. Using the UK Biobank (UKB) 368,865 whole-exome sequences of white British ancestry and AD-by-proxy (57,976 proxy AD cases and 310,889 non-AD proxy controls), we conducted the largest exome-wide association study of proxy AD to date. We identified 38 novel genes harboring rare variants for AD, such as ANKRD36 (P = 6.02 x 10-31), MMP13 (P = 1.08 x 10-6), TUBA4A (P = 7.15 x 10-12), and ZNF296 (P = 4.19 x 10-14), demonstrating the power boost of aggregating rare variants and utilizing AD-by-proxy in gene discovery. We further replicated these genes in the FinnGen dataset. Notably, MMP13 is a current drug target for AD and TUBA4A is a drug target for cognitive impairment in clinical trials. These results expand our knowledge of the genetic architecture of AD, especially the role of rare variants, and potential drug targets for AD.