An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access.

Purpose: Advanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.
Methods: Collective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.
Results: Type 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.
Conclusions: The relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.
Competing Interests: The authors have declared that no competing interests exist: Tom Southerington Enni Makkonen Roosa E. Kallionpää Pauli Wihuri Theresa Knopp Marco Hautalahti Johanna Mäkelä Arto Mannermaa Erna Mäkinen Anne-Mari Moilanen Authors with competing interests I have read the journal’s policy and the authors of this manuscript have the following competing interests: Amy Jones: employee and share holder of Gyroscope Therapeutics Ltd Darin Curtiss: employee and share holder of Gyroscope Therapeutics Ltd Claire Harris: employee and share holder of Gyroscope Therapeutics Ltd, Research grant from RA Phaemaceutics (payment to institution), Royalty income from commercialized factor I ELISA; Hycult Biotech, consultancy income from Q32 Bio Inc, Chinook Therapeutics, and Biocryst Pharmaceuticals (all payment to institution), Nadia Waheed: employee and share holder of Gyroscope Therapeutics Ltd, grants from Carl Zeiss Meditec, Topcon, Regeneron, Heidelberg, Nidek, Optovue, consultancy income from Apellis, Nidek, Boehringer Ingelheim, stock in Ocudyne.