title: Population-based analysis of Alzheimer's disease risk alleles implicates genetic interactions.
abstract: BACKGROUND
  Reported odds ratios and population attributable fractions (PAF) for late-onset Alzheimer's disease (LOAD) risk loci (BIN1, ABCA7, CR1, MS4A4E, CD2AP, PICALM, MS4A6A, CD33, and CLU) come from clinically ascertained samples. Little is known about the combined PAF for these LOAD risk alleles and the utility of these combined markers for case-control prediction. Here we evaluate these loci in a large population-based sample to estimate PAF and explore the effects of additive and nonadditive interactions on LOAD status prediction performance.
  
  
  METHODS
  2419 samples from the Cache County Memory Study were genotyped for APOE and nine LOAD risk loci from AlzGene.org. We used logistic regression and receiver operator characteristic analysis to assess the LOAD status prediction performance of these loci using additive and nonadditive models and compared odds ratios and PAFs between AlzGene.org and Cache County.
  
  
  RESULTS
  Odds ratios were comparable between Cache County and AlzGene.org when identical single nucleotide polymorphisms were genotyped. PAFs from AlzGene.org ranged from 2.25% to 37%; those from Cache County ranged from .05% to 20%. Including non-APOE alleles significantly improved LOAD status prediction performance (area under the curve = .80) over APOE alone (area under the curve = .78) when not constrained to an additive relationship (p < .03). We identified potential allelic interactions (p values uncorrected): CD33-MS4A4E (synergy factor = 5.31; p < .003) and CLU-MS4A4E (synergy factor = 3.81; p < .016).
  
  
  CONCLUSIONS
  Although nonadditive interactions between loci significantly improve diagnostic ability, the improvement does not reach the desired sensitivity or specificity for clinical use. Nevertheless, these results suggest that understanding gene-gene interactions may be important in resolving Alzheimer's disease etiology.
authors: Department of Biology, Brigham Young University, Provo; ARUP Institute for Clinical and Experimental Pathology, Utah State University, Logan, Utah.
authors: Mark T W
authors: MT
authors: Ebbert
authors: Department of Biology, Brigham Young University, Provo; ARUP Institute for Clinical and Experimental Pathology, Utah State University, Logan, Utah.
authors: Perry G
authors: PG
authors: Ridge
authors: ARUP Institute for Clinical and Experimental Pathology, Utah State University, Logan, Utah.
authors: Andrew R
authors: AR
authors: Wilson
authors: Department of Biology, Brigham Young University, Provo.
authors: Aaron R
authors: AR
authors: Sharp
authors: Department of Biology, Brigham Young University, Provo.
authors: Matthew
authors: M
authors: Bailey
authors: Department of Family Consumer and Human Development, Utah State University, Logan, Utah; Center for Epidemiologic Studies, Utah State University, Logan, Utah.
authors: Maria C
authors: MC
authors: Norton
authors: Department of Psychology, Utah State University, Logan, Utah; Center for Epidemiologic Studies, Utah State University, Logan, Utah.
authors: JoAnn T
authors: JT
authors: Tschanz
authors: Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, Utah; Center for Epidemiologic Studies, Utah State University, Logan, Utah.
authors: Ronald G
authors: RG
authors: Munger
authors: Department of Mathematics and Statistics, Utah State University, Logan, Utah; Center for Epidemiologic Studies, Utah State University, Logan, Utah.
authors: Christopher D
authors: CD
authors: Corcoran
authors: Department of Biology, Brigham Young University, Provo. Electronic address: kauwe@byu.edu.
authors: John S K
authors: JS
authors: Kauwe
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012306:Risk
chemical_list: D001057:Apolipoproteins E
keywords: Alzheimer’s disease; epistasis; genetic interactions; odds ratio; population attributable fraction; risk
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