title: 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.
authors.affiliation: Medical Scientist Training Program, Center for Human Genetics and Research, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA, maryellen.koran@gmail.com.
authors.forename: Mary Ellen I
authors.initials: ME
authors.lastname: Koran
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hohman
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D015203:Reproducibility of Results; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel
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