Abstract
Purpose :
Age related macular degeneration (AMD) and Alzheimer’s disease (AD) are both neurodegenerative diseases that significantly impact the aging US population. We investigated the shared genetic underpinnings by integrating summary statistics of two large GWAS, namely the International AMD Genomics Consortium (IAMDGC) and the International Genomics of Alzheimer’s Project (IGAP).
Methods :
Summary statistics for AMD were obtained from the IAMDGC (Fritsche et al., 2016), involving 26 datasets with 16,144 AMD cases and 17,832 controls of European ancestry. AD summary statistics were used from IGAP (Kunkle et al., 2019), with 46 datasets comprising 35,274 cases and 59,163 controls of non-Hispanic Whites. Multi-Trait Analysis of GWAS (MTAG) was employed based on previously established methods. Two analyses were conducted, with AMD and AD alternatively set as the primary trait in each analysis. Functional mapping and annotation (FUMA) were used to identify genes associated with significant single nucleotide polymorphisms (SNPs) and causal variants from the pleiotropy, revealing common genes and SNPs between AD and AMD. Further downstream analysis was done with Ingenuity Pathway Analysis (IPA). Significant pathways (p <0.05) were compared between AMD and AD MTAG analyses to pinpoint shared pathways.
Results :
The AMD primary MTAG analysis followed by FUMA revealed 119 significant genes. Lead SNPs were located in associated genes including CFHR3 and PLEKHA1 (p<10-8). In the AD primary MTAG analysis, 19 significant genes were identified. Lead SNPs were located in associated genes such as CFH and MARK4. (p<10-8). Pleiotropy between AMD and AD by MTAG analyses identified 14 shared, independently significant genes and 7 shared, independently significant SNPs with genome-wide significance. These 14 genes were CFH, CFHR2, CFHR4, CFHR5, CFHR3, ARMS2, HTRA1, CFHR1, KCNT2, CNN2, ABCA7, F13B, ASPM, and ZBTB4. IPA analysis demonstrated that a top shared pathway was complement.
Conclusions :
Our study uncovers shared genetic risk factors between AMD and AD, providing valuable insights into overlapping pathophysiology of these complex disorders. The identified common genes may offer potential targets for further research and therapeutic development.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.