Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography

Abstract

Late-onset Alzheimer's disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer's disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD's genetic etiology. Subsets of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidogenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid-calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.

Figure 1. The Effect of Genetic Interactions between RYR3 and CACNA1C on Amyloid Deposition

In all three datasets, a minor allele in both genes corresponded to higher amyloid load versus a minor allele in only one or none of the genes. Bars represent one standard error. Fig. 1a Effect of RYR3 (rs16972835) and CACNA1C (rs2302729) on Amyloid Deposition (measured by AV-45 ligand) in Discovery Dataset. Fig 1b Effect of RYR3 (rs12901404) and CACNA1C (rs7132154) on Amyloid Deposition (measured by AV-45 ligand) in Stage 1 Validation Dataset. Fig 1c Effect of RYR3 (rs16972835) and CACNA1C (rs7132154) on Amyloid Deposition (measured by PiB ligand) in Stage 2 Validation Dataset.

Figure 1. The Effect of Genetic Interactions between RYR3 and CACNA1C on Amyloid Deposition

In all three datasets, a minor allele in both genes corresponded to higher amyloid load versus a minor allele in only one or none of the genes. Bars represent one standard error. Fig. 1a Effect of RYR3 (rs16972835) and CACNA1C (rs2302729) on Amyloid Deposition (measured by AV-45 ligand) in Discovery Dataset. Fig 1b Effect of RYR3 (rs12901404) and CACNA1C (rs7132154) on Amyloid Deposition (measured by AV-45 ligand) in Stage 1 Validation Dataset. Fig 1c Effect of RYR3 (rs16972835) and CACNA1C (rs7132154) on Amyloid Deposition (measured by PiB ligand) in Stage 2 Validation Dataset.

Figure 1. The Effect of Genetic Interactions between RYR3 and CACNA1C on Amyloid Deposition

In all three datasets, a minor allele in both genes corresponded to higher amyloid load versus a minor allele in only one or none of the genes. Bars represent one standard error. Fig. 1a Effect of RYR3 (rs16972835) and CACNA1C (rs2302729) on Amyloid Deposition (measured by AV-45 ligand) in Discovery Dataset. Fig 1b Effect of RYR3 (rs12901404) and CACNA1C (rs7132154) on Amyloid Deposition (measured by AV-45 ligand) in Stage 1 Validation Dataset. Fig 1c Effect of RYR3 (rs16972835) and CACNA1C (rs7132154) on Amyloid Deposition (measured by PiB ligand) in Stage 2 Validation Dataset.