Kwangsik Nho1,2,3, Kelly Nudelman1,3,4,5, Mariet Allen6, Angela Hodges7, Sungeun Kim1,2,3,8, Shannon L Risacher1,3, Liana G Apostolova1,3, Kuang Lin7, Katie Lunnon9, Xue Wang10, Jeremy D Burgess6, Nilüfer Ertekin-Taner6,11, Ronald C Petersen12, Lisu Wang13, Zhenhao Qi13, Aiqing He13, Isaac Neuhaus13, Vishal Patel13, Tatiana Foroud2,3,4,5, Kelley M Faber4,5, Simon Lovestone14, Andrew Simmons7, Michael W Weiner15,16, Andrew J Saykin1,3,4. 1. Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana. 2. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana. 3. Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana. 4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana. 5. National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University, Indiana. 6. Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida. 7. Psychology & Neuroscience, Institute of Psychiatry, King's college London, London, UK. 8. Department of Electrical and Computer Engineering, State University of New York, Oswego, New York. 9. University of Exeter Medical School, Exeter, UK. 10. Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, Florida. 11. Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida. 12. Department of Neurology, Mayo Clinic Minnesota, Rochester, Minnesota. 13. Bristol-Meyers Squibb, Wallingford, Connecticut. 14. Department of Psychiatry, University of Oxford, London, UK. 15. Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, California. 16. Department of Veterans Affairs Medical Center, San Francisco, California.
Abstract
INTRODUCTION: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD). METHODS: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. RESULTS: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10-8 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18 F]Florbetapir positron emission tomography and CSF Aβ1-42 . DISCUSSION: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
INTRODUCTION: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD). METHODS: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. RESULTS: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10-8 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18 F]Florbetapir positron emission tomography and CSF Aβ1-42 . DISCUSSION: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
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