title: Genetic modification of the relationship between phosphorylated tau and neurodegeneration.
abstract: BACKGROUND
  A subset of individuals present at autopsy with the pathologic features of Alzheimer's disease having never manifest the clinical symptoms. We sought to identify genetic factors that modify the relationship between phosphorylated tau (PTau) and dilation of the lateral inferior ventricles.
  
  
  METHODS
  We used data from 700 subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). A genome-wide association study approach was used to identify PTau × single nucleotide polymorphism (SNP) interactions. Variance explained by these interactions was quantified using hierarchical linear regression.
  
  
  RESULTS
  Five SNP × PTau interactions passed a Bonferroni correction, one of which (rs4728029, POT1, 2.6% of variance) was consistent across ADNI-1 and ADNI-2/GO subjects. This interaction also showed a trend-level association with memory performance and levels of interleukin-6 receptor.
  
  
  CONCLUSIONS
  Our results suggest that rs4728029 modifies the relationship between PTau and both ventricular dilation and cognition, perhaps through an altered neuroinflammatory response.
authors.affiliation: The Center for Human Genetics Research, Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: Timothyjhohman@gmail.com.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hohman
authors.affiliation: The Center for Human Genetics Research, Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Mary Ellen I
authors.initials: ME
authors.lastname: Koran
authors.affiliation: The Center for Human Genetics Research, Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020547:Lateral Ventricles / Q000473:pathology*; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D009410:Nerve Degeneration / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D016875:tau Proteins
keywords: Alzheimer's disease; CSF; GWAS; Genetic interactions; Imaging genetics; MRI; Memory; Phosphorylated tau; Plasma; Quantitative traits; Ventricular volume