title: Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease.
abstract: Previous research implicates alterations in oxidative phosphorylation (OXPHOS) in the development of Alzheimer's disease (AD). We sought to test whether genetic variants within OXPHOS genes increase the risk of AD. We first used gene-set enrichment analysis to identify associations, and then applied a previously replicated stroke genetic risk score to determine if OXPHOS genetic overlap exists between stroke and AD. Gene-set enrichment analysis identified associations between variation in OXPHOS genes and AD versus control status (p = 0.012). Conversion from cognitively normal controls to mild cognitive impairment was also associated with the OXPHOS gene-set (p = 0.045). Subset analyses demonstrated association for complex I genes (p < 0.05), but not for complexes II-V. Among neuroimaging measures, hippocampal volume and entorhinal cortex thickness were associated with OXPHOS genes (all p < 0.025). The stroke genetic risk score demonstrated association with clinical status, baseline and longitudinal imaging measures (p < 0.05). OXPHOS genetic variation influences clinical status and neuroimaging intermediates of AD. OXPHOS genetic variants associated with stroke are also linked to AD progression. Further studies are needed to explore functional consequences of these OXPHOS variants.
authors.affiliation: Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. Electronic address: abiffi@partners.org.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Mert R
authors.initials: MR
authors.lastname: Sabuncu
authors.affiliation: Department of Radiology, University of California, San Diego, CA, USA.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Schmansky
authors.affiliation: Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Salat
authors.affiliation: Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
authors.affiliation: Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology; D042967:Electron Transport Complex I / Q000235:genetics*; D018728:Entorhinal Cortex / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D009929:Organ Size / Q000235:genetics; D010085:Oxidative Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D020521:Stroke / Q000235:genetics*
chemical_list: D042967:Electron Transport Complex I
keywords: Alzheimer's disease; Genes; Mitochondria; OXPHOS; Stroke