Cameron Schmutz and Dr. Keoni Kauwe, Biology Department
INTRODUCTION
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder and is the leading cause of dementia.1,3 It is the sixth leading cause of death in the United States and is the only one that has no adequate prevention or cure. AD is characterized by a progressive loss in cognitive function and memory loss. Neuropathological symptoms include loss of neurons and synapses, extensive accumulation of amyloid plaques and neurofibrillary tangles. Alzheimer’s disease has been identified as a proteopathy disease due to the extensive accumulation of amyloid plaques and neurofibrillary tangles.1,2,3 This project focused on the research of a rare genetic variant in the PLD3 gene, namely, rs145999145, which shows increased risk factors for AD. In collaboration with Genetech and multiple other organizations, we performed single-nucleotide polymorphism (SNP) genotyping and analysis on thousands of DNA samples from the Cache County Study on Memory Health and Aging. Our results supported the hypothesis that rs145999145 played a large role in the development of AD. The results of our study and the results of our collaborators were published in Nature in December 2013.
METHODS
2.1 Subjects
Our data set was drawn from The Cache County Study on Memory health and Aging. The Cache County Study is a large population-based study that was initiated in 1994 to investigate the association of APOE genotype and environmental exposures on cognitive function and dementia. The 5,092 subjects were taken from Cache County, Utah where 90% of all residents over 65 participated. Tests to determine cognitive function were given triennially over a period of 15 years. In addition to administering tests, the study also prepared a pedigree that linked participants with their parents, siblings, children and relatives. There are over 600 confirmed AD cases in the cohort.
2.2 Genotyping
We performed SNP genotyping on all 600 AD cases from the Cache County Study and the approximately 3400 controls for rs145999145 using a custom TaqMan assay.
RESULTS
In our final results we only included SNPs with a genotyping call rate higher than 98% and in Hardy-Weinberg equilibrium for analysis. Due to this we found 6 carriers out of 259 AD Cases with a carrier frequency percentage of 2.35. Out of 2442 controls we found 29 cases with a carrier frequency % of 1.17. We had an OR (95% Cl) of 2.03 with a p-value 0.131.
These results along with those of our collaborators show a significant association with rs145999145 and a two-fold increased risk in the development of Alzheimer’s disease.
DISCUSSION
This work further supports the increased risk for AD found from mutations on the PLD3 gene. The PLD3 gene is found throughout the brain in areas that are highly vulnerable to AD, which include the hippocampus and cortex. With rs145999145 being significant to the development of AD, this adds to our understanding of AD pathology and hopefully brings us closer to finding a treatment for this devastating disease.
CONCLUSION
Despite this being a valuable find, much about AD pathology is unknown and has yet to be discovered. Using SNP genotyping to find variants that contribute to AD risk is continually adding to researchers further knowledge of AD. This study will hopefully provide useful information for future preventative and therapeutic efforts toward the curing of AD.
The complete study published in nature can be found here:
http://www.nature.com/nature/journal/v505/n7484/pdf/nature12825.pdf