Genotype patterns atPICALM, CR1, BIN1, CLU, andAPOEgenes are associated with episodic memory
Year: 2012
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes. METHODS: Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education. RESULTS: Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (β = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (β = -0.44, SE = 0.09, p = 0.009 and β = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (β = 0.26, SE = 0.10, p = 0.010). CONCLUSIONS: MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.
Source: Neurology
Authors: S. Barral, T. Bird, A. Goate, M.R. Farlow, R. Diaz-Arrastia, D.A. Bennett, N. Graff-Radford, B.F. Boeve, R.A. Sweet, Y. Stern, R.S. Wilson, T. Foroud, J. Ott, R. Mayeux, Robert Green, Neil Kowall, Lindsay Farrer, Jennifer Williamson, Vincent Santana, Donald Schmechel, Peter Gaskel, Bernardino Ghetti, Martin R. Farlow, Kelley Faber, Heather Prentice, Kelly Horner, John H. Growdon, Deborah Blacker, Rudolph E. Tanzi, Bradley T. Hyman, Bradley Boeve, Karen Kuntz, Lindsay Norgaard, Nathan Larson, Dana Kistler, Francine Parfitt, Jenny Haddow, Jeremy Silverman, Michal Schnaider Beeri, Mary Sano, Joy Wang, Rachel Lally, Nancy Johnson, Marcel Mesulam, Sandra Weintraub, Eileen Bigio, Jeffery Kaye, Patricia Kramer, Jessica Payne-Murphy, David Bennett, Holli Jacobs, Jeen-Soo Chang, Danielle Arends, Lindy Harrell, George Bartzokis, Jeffery Cummings, Po H. Lu, Usha Toland, Charles Smith, Alise Brickhouse, John Trojanowski, Vivianna Van Deerlin, Elisabeth McCarty Wood, Steven DeKosky, Robert Sweet, Elise Weamer, Helena Chui, Arousiak Varpetian, Ramon Diaz-Arrastia, Roger Rosenberg, Barbara Davis, Thomas Bird, Gerard D. Schellenberg, Murray Raskind, Malia Rumbaugh, Kate Nickel, Alison Goate, John Morris, Joanne Norton, Denise Levitch, Betsy Grant, Mary Coats, Allen Levey, Ami Rosen, Ezinna Anosike
Institutions: University of Washington, VA Puget Sound Health Care System, Columbia University, Washington University in St. Louis, Indiana University, The University of Texas Southwestern Medical Center, Rush University, Mayo Clinic in Florida, Mayo Clinic, University of Pittsburgh, Indiana University – Purdue University Indianapolis, Boston University, Duke University, Massachusetts General Hospital, Icahn School of Medicine at Mount Sinai, Northwestern University, Northwestern University, Oregon Health & Science University, University of Alabama, University of California, Los Angeles, University of Kentucky, University of Pennsylvania, University of Southern California, Emory University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, American Academy of Neurology, Danone, Rush University, National Natural Science Foundation of China, Elan, Eisai, Astellas Pharma, National Institutes of Health, Allergan, National Institute on Aging, National Human Genome Research Institute
Awards: G1147558203, G1282666458, G1309605592, Indiana Alzheimer Disease Center, G1612041964, G2101661345, G2200385677, G2422713368, Neurobiology of Alzheimer's Disease and Aging, Alzheimer's Disease Research Center, ADCC Genomic Medicine Approach to MCI and Dementia, G3354629377, Alzheimer's Disease Research Center, G3632542342, G3743240706, G384347443, G3919444319, G4000272535, G4094333107, G413369726, Alzheimer's Disease Core Center, G453222670, Risk Factors, Pathology, and Clinical Expressions of AD, Oregon Alzheimer's Disease Center, Alzheimer's Disease Genetics Consortium, G532877393, G561739401, G5977822913, Epidemiology of Familial Late-Onset Alzheimer's Disease, G611802359, Alzheimer's Disease Research Center - Overall, Prediction of Psychosis in Alzheimer Disease, Alzheimer's Disease Research Center, Alzheimer Disease Research Center, Genetic Consortium for Late Onset Alzheimer's Disease, Boston University Alzheimer's Disease Center, Alzheimer's Disease Research Center, Alzheimer's Disease Core Center, G8267674335, G828200374, G8678021017, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), Mayo Alzheimer's Disease Research Center, G983864884
OpenAlex ID: W2085843402