Original Article

Translational Stroke Research

, Volume 3, Supplement 1, pp 102-112

First online:

TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer’s Disease

  • Valerie ValantAffiliated withDivision of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General HospitalCenter for Human Genetic Research, Massachusetts General HospitalHemorrhagic Stroke Research Group, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute
  • , Brendan T. KeenanAffiliated withProgram in Medical and Population Genetics, Broad InstituteProgram in Translational NeuroPsychiatric Genomics, Institute for Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital and Harvard Medical School
  • , Christopher D. AndersonAffiliated withDivision of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General HospitalCenter for Human Genetic Research, Massachusetts General HospitalHemorrhagic Stroke Research Group, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute
  • , Joshua M. ShulmanAffiliated withProgram in Medical and Population Genetics, Broad InstituteProgram in Translational NeuroPsychiatric Genomics, Institute for Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital and Harvard Medical School
  • , William J. DevanAffiliated withDivision of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General HospitalCenter for Human Genetic Research, Massachusetts General HospitalHemorrhagic Stroke Research Group, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute
  • , Alison M. AyresAffiliated withHemorrhagic Stroke Research Group, Massachusetts General Hospital
  • , Kristin SchwabAffiliated withHemorrhagic Stroke Research Group, Massachusetts General Hospital
  • , Joshua N. GoldsteinAffiliated withDivision of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General HospitalHemorrhagic Stroke Research Group, Massachusetts General HospitalDepartment of Emergency Medicine, Massachusetts General Hospital
  • , Anand ViswanathanAffiliated withHemorrhagic Stroke Research Group, Massachusetts General Hospital
    • , Steven M. GreenbergAffiliated withHemorrhagic Stroke Research Group, Massachusetts General Hospital
    • , David A. BennettAffiliated withRush Alzheimer’s Disease Center, Department of Neurological Science, Rush University medical Center
    • , Philip L. De JagerAffiliated withProgram in Medical and Population Genetics, Broad InstituteProgram in Translational NeuroPsychiatric Genomics, Institute for Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital and Harvard Medical School
    • , Jonathan RosandAffiliated withDivision of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General HospitalCenter for Human Genetic Research, Massachusetts General HospitalHemorrhagic Stroke Research Group, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute Email author 
    • , Alessandro BiffiAffiliated withDivision of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General HospitalCenter for Human Genetic Research, Massachusetts General HospitalHemorrhagic Stroke Research Group, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute
    • , the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

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Abstract

Cerebral amyloid angiopathy (CAA) related intracerebral hemorrhage (ICH) is a devastating form of stroke with no known therapies. Clinical, neuropathological, and genetic studies have suggested both overlap and divergence between the pathogenesis of CAA and the biologically related condition of Alzheimer’s disease (AD). Among the genetic loci associated with AD are APOE and TOMM40, a gene in close proximity to APOE. We investigate here whether variants within TOMM40 are associated with CAA-related ICH and CAA neuropathology. Using cohorts from the Massachusetts General Hospital (MGH) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we designed a comparative analysis of high-density SNP genotype data for CAA-related ICH and AD. APOE ε4 was associated with CAA-related ICH and AD, while APOE ε2 was protective in AD but a risk factor for CAA. A total of 14 SNPs within TOMM40 were associated with AD (p < 0.05 after multiple testing correction), but not CAA-related ICH (all p > 0.20); as a result, all AD-associated SNPs within TOMM40 showed heterogeneity of effect in CAA-related ICH (BD p < 0.001). Analysis of CAA neuropathology in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), however, found that neuritic plaque, diffuse plaque burden, and vascular amyloid burden associated with all TOMM40 SNPs (p < 0.02). These results suggest that alterations in TOMM40 can promote vascular as well as plaque amyloid deposition, but not the full pathogenic pathway leading to CAA-related ICH.

Keywords

TOMM40 APOE Cerebral amyloid angiopathy Alzheimer’s disease Linkage disequilibrium