Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium

Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 × ABCB1, PSAP × PEBP4, and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.

[1]  H. Nakanishi,et al.  Mutation analysis of the MYO7A and CDH23 genes in Japanese patients with Usher syndrome type 1 , 2010, Journal of Human Genetics.

[2]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[3]  V Shane Pankratz,et al.  Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions. , 2011, Journal of Alzheimer's disease : JAD.

[4]  A. Smith,et al.  Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer’s disease , 2004, Journal of Medical Genetics.

[5]  P. Deloukas,et al.  Interactions between PPAR-α and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epistasis Project. , 2012, International journal of molecular epidemiology and genetics.

[6]  Ian F. Harrison,et al.  Prazosin, an α1-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease , 2013, Neurobiology of Aging.

[7]  S. Rivest,et al.  The role of ABCB1 and ABCA1 in beta-amyloid clearance at the neurovascular unit in Alzheimer's disease , 2013, Front. Physiol..

[8]  L. Fratiglioni,et al.  Role of genes and environments for explaining Alzheimer disease. , 2006, Archives of general psychiatry.

[9]  P. Deloukas,et al.  Interaction of insulin and PPAR-α genes in Alzheimer’s disease: the Epistasis Project , 2012, Journal of Neural Transmission.

[10]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[11]  Jun Wang,et al.  Neuronal SIRT1 Activation as a Novel Mechanism Underlying the Prevention of Alzheimer Disease Amyloid Neuropathology by Calorie Restriction* , 2006, Journal of Biological Chemistry.

[12]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[13]  Diana Wang,et al.  SIRT1 Suppresses b-Amyloid Production by Activating the a-Secretase Gene ADAM10 , 2010 .

[14]  Tim Becker,et al.  INTERSNP: genome-wide interaction analysis guided by a priori information , 2009, Bioinform..

[15]  Richard J. Caselli,et al.  Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers , 2011, NeuroImage.

[16]  Nick C Fox,et al.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease , 2013, Nature Genetics.

[17]  S. Nishio,et al.  Prevalence and Clinical Features of Hearing Loss Patients with CDH23 Mutations: A Large Cohort Study , 2012, PloS one.

[18]  R. Petersen,et al.  Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease , 2010, Human Genetics.

[19]  Winnie S. Liang,et al.  GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. , 2007, Neuron.

[20]  Carlos Cruchaga,et al.  The epigenetic landscape of Alzheimer's disease , 2014, Nature Neuroscience.

[21]  D. Selkoe Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[22]  O. Combarros,et al.  Interaction between dopamine β-hydroxylase and interleukin genes increases Alzheimer’s disease risk , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[23]  Timothy J. Hohman,et al.  Epistatic Genetic Effects among Alzheimer’s Candidate Genes , 2013, PloS one.

[24]  R. Lakshmy,et al.  MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction , 2012, Neurobiology of Aging.

[25]  M. Owen,et al.  Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[26]  G. Annoni,et al.  Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer’s disease , 2004, Neurobiology of Aging.

[27]  L. Guarente,et al.  RETRACTED: SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10 , 2010, Cell.

[28]  H. Kroemer,et al.  MDR1‐P‐Glycoprotein (ABCB1) Mediates Transport of Alzheimer’s Amyloid‐β Peptides—Implications for the Mechanisms of Aβ Clearance at the Blood–Brain Barrier , 2007, Brain pathology.

[29]  P. Crane,et al.  Alzheimer’s Disease: Analyzing the Missing Heritability , 2013, PloS one.

[30]  D. G. Clark,et al.  Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease , 2011, Nature Genetics.

[31]  P. Sham,et al.  Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases , 2011, Genetic epidemiology.

[32]  P. Deloukas,et al.  The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project , 2010, BMC Medical Genetics.

[33]  Marylyn D. Ritchie,et al.  Genomic analyses with biofilter 2.0: knowledge driven filtering, annotation, and model development , 2013, BioData Mining.

[34]  A. Dudarewicz,et al.  Genetic Variants of CDH23 Associated With Noise-Induced Hearing Loss , 2014, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[35]  Winnie S. Liang,et al.  GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers , 2007, Neuron.

[36]  Eric M Reiman,et al.  Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment. , 2007, Archives of neurology.

[37]  L. Baki,et al.  Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Gambardella,et al.  Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease , 2013, Journal of Neural Transmission.

[39]  P. Riekkinen,et al.  Effects of combined block of alpha 1-adrenoceptors and NMDA receptors on spatial and passive avoidance behavior in rats. , 1996, European journal of pharmacology.

[40]  Zhiqiang Wang,et al.  Emerging Roles of SIRT1 in Cancer Drug Resistance. , 2013, Genes & cancer.

[41]  L. Y. Wang,et al.  ABCB1 Genotype and CSF β-Amyloid in Alzheimer Disease , 2011, Journal of geriatric psychiatry and neurology.

[42]  Shashwath A Meda,et al.  Genetic interactions within inositol-related pathways are associated with longitudinal changes in ventricle size. , 2013, Journal of Alzheimer's disease : JAD.

[43]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[44]  Tricia A. Thornton-Wells,et al.  Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography , 2013, Human Genetics.

[45]  Marylyn D. Ritchie,et al.  Pacific Symposium on Biocomputing 14:368-379 (2009) BIOFILTER: A KNOWLEDGE-INTEGRATION SYSTEM FOR THE MULTI-LOCUS ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES * , 2022 .

[46]  D. Stephan,et al.  Genetic control of human brain transcript expression in Alzheimer disease. , 2009, American journal of human genetics.