GWAS of cataract in Puerto Ricans identifies a novel large-effect variant in ITGA6

Cataract is a common cause of vision loss and affects millions of people worldwide. Genome-wide association studies (GWAS) and family studies of cataract have demonstrated a role for genetics in cataract susceptibility. However, most of these studies have been conducted in populations of European or Asian descent, leaving the genetic etiology of cataract among Hispanic/Latino (HL) populations unclear. Here we perform the first GWAS of cataract in a Puerto Rican population of research participants derived from the customer base of 23andMe, Inc. In our analysis with 3,060 self-reported cases and 41,890 controls, we found a novel association of large effect size with a rare coding variant in the ITGA6 gene (rs200560853, p-value=2.9×10−12, OR=12.7, 95% CI=[6.5, 24.7]). ITGA6 is part of the integrin alpha chain in the laminin receptor subfamily, and likely contributes to eye lens homeostasis, transparency, and cell survival. We found that this coding variant is associated with a 13.7 year earlier disease onset on average, as well as a 4.3-fold higher rate of cataract events in the Puerto Rican population. The variant has a minor allele frequency (MAF) of 0.089% in Puerto Rico and is extremely rare elsewhere in the world. Population genetic analyses showed that the variant is only found in individuals with ancestry from the Americas and countries bordering the Mediterranean Sea, suggesting a North African origin. Our discovery identifies a novel genetic risk factor for cataract in Puerto Ricans and highlights the importance of including underrepresented populations in genomics research to improve our understanding of disease in all populations. ### Competing Interest Statement All authors are employed by and hold stock or stock options in 23andMe, Inc. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Eligible research participants were selected from the 23andMe customer base who provided informed consent and volunteered to participate in the research online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent (E&I) Review Services. As of 2022, E&I Review Services is part of Salus IRB (). Inclusion criteria of the research participants was based on their consent status at the time when the data analysis was initiated. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes