Abstract
We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
| Original language | English (US) |
|---|---|
| Article number | 107908 |
| Journal | Cell reports |
| Volume | 32 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 14 2020 |
Keywords
- Alzheimer's disease
- RNA-seq
- aging
- coexpression analysis
- differential expression analysis
- meta-analysis
- mouse models
- neuroinflammation
- transcriptome
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models. / Accelerating Medicines Partnership-Alzheimer's Disease Consortium.
In: Cell reports, Vol. 32, No. 2, 107908, 14.07.2020.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models
AU - Accelerating Medicines Partnership-Alzheimer's Disease Consortium
AU - Wan, Ying Wooi
AU - Al-Ouran, Rami
AU - Mangleburg, Carl G.
AU - Perumal, Thanneer M.
AU - Lee, Tom V.
AU - Allison, Katherine
AU - Swarup, Vivek
AU - Funk, Cory C.
AU - Gaiteri, Chris
AU - Allen, Mariet
AU - Wang, Minghui
AU - Neuner, Sarah M.
AU - Kaczorowski, Catherine C.
AU - Philip, Vivek M.
AU - Howell, Gareth R.
AU - Martini-Stoica, Heidi
AU - Zheng, Hui
AU - Mei, Hongkang
AU - Zhong, Xiaoyan
AU - Kim, Jungwoo Wren
AU - Dawson, Valina L.
AU - Dawson, Ted M.
AU - Pao, Ping Chieh
AU - Tsai, Li Huei
AU - Haure-Mirande, Jean Vianney
AU - Ehrlich, Michelle E.
AU - Chakrabarty, Paramita
AU - Levites, Yona
AU - Wang, Xue
AU - Dammer, Eric B.
AU - Srivastava, Gyan
AU - Mukherjee, Sumit
AU - Sieberts, Solveig K.
AU - Omberg, Larsson
AU - Dang, Kristen D.
AU - Eddy, James A.
AU - Snyder, Phil
AU - Chae, Yooree
AU - Amberkar, Sandeep
AU - Wei, Wenbin
AU - Hide, Winston
AU - Preuss, Christoph
AU - Ergun, Ayla
AU - Ebert, Phillip J.
AU - Airey, David C.
AU - Mostafavi, Sara
AU - Yu, Lei
AU - Klein, Hans Ulrich
AU - Carter, Gregory W.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information: The results published here are in part based on data obtained from the AMP-AD Knowledge Portal (https://doi.org/10.7303/syn2580853). ROSMAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by National Institute on Aging (NIA) grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, and U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. Mayo RNA-seq study data were provided by the following sources: the Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, Florida, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949; National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820; the CurePSP Foundation; and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the NIA (P30 AG19610, Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. Mount Sinai Brain Bank (MSBB) data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt of the Mount Sinai School of Medicine through funding from NIA grant U01AG046170. Furthermore, Emory study data were supported through funding from NIA grants P50 AG025688, U01 AG046161, and U01 AG061357. This study was also supported in part by grants from the NIH (R01AG053960, R01AG050631, R01AG057339, U01AG046161, U01 AG046139, RF1AG054014, RF1 AG057440, R01AG057473, R01AG057914, P50 NS38377, and F31AG050357). C.G.M. was supported by the Cullen Foundation and the Baylor College of Medicine Medical Scientist Training Program (MSTP). J.M.S. was additionally supported by grants from the Huffington Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, and a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Z.L. received additional support from the National Science Foundation, Division of Mathematical Sciences (DMS-1263932), the Cancer Prevention Research Institute of Texas (RP170387), the Houston Endowment, and the Neurodegeneration Consortium and Belfer Family Foundation. T.M.D. is supported by the JPB Foundation and is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation of the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with the Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the foundation's Parkinson's Disease Program (M-2014). We are grateful to Dr. Bruce Yankner for contributing additional mouse RNA-seq data. This study is part of the NIA AMP-AD, MODEL-AD, and Resilience-AD programs. Conceptualization, D.A.C. T.E.G. A.I.L. D.A.B. K.E. Z.L. B.Z. E.S. P.L.D.J. N.D.P. N.E.-T. Y.-W.W. J.M.S. B.A.L. T.M.P. C.G. M.W. L.M.M. S.K.S. K.D.D. and P.J.E.; Methodology and Data Curation, Y.-W.W. R.A.-O. T.V.L. K.A. Z.L. B.A.L. T.M.P. V.S. M.W. C.C.F. C.G. M.A. P.S. Y.C. and X.W.; Formal Analysis, Y.-W.W. R.A.-O. C.G.M. B.A.L. J.A.E. K.D.D. P.J.E. and P.S.; Writing – Original Draft, Y.-W.W. C.G.M. R.A.-O. T.V.L. J.M.S. B.A.L. T.M.P. M.A. N.E.-T. L.M.M. A.I.L. D.A.B. P.L.D.J. J.M.S. and G.W.C.; Writing – Review & Editing, C.G.M. R.A.-O. J.M.S. Z.L. T.V.L. K.A. S.M.N. C.C.K. H.Z. V.L.D. A.I.L. B.A.L. T.M.P. M.A. N.E.-T. L.M.M. D.A.B. P.L.D.J. J.M.S. and G.W.C.; Funding Acquisition, J.M.S. Z.L. L.M.M. B.A.L. A.I.L. and T.E.G.; Resources, S.M.N. C.C.K. V.M.P. G.R.H. H.M.-S. H.Z. J.W.K. V.L.D. T.M.D. P.-C.P. L.-H.T. J.-V.H.-M. M.W. M.E.E. H.M. X.Z. P.C. Y.L. T.E.G. B.A.L. and L.M.M.; Supervision, J.M.S. Z.L. B.A.L. and L.M.M. The authors declare no competing interests. Funding Information: The results published here are in part based on data obtained from the AMP-AD Knowledge Portal ( https://doi.org/10.7303/syn2580853 ). ROSMAP study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by National Institute on Aging (NIA) grants P30AG10161 , R01AG15819 , R01AG17917 , R01AG30146 , R01AG36836 , U01AG32984 , and U01AG46152 , the Illinois Department of Public Health , and the Translational Genomics Research Institute . Mayo RNA-seq study data were provided by the following sources: the Mayo Clinic Alzheimer’s Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, Florida, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer’s Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574 , R01 AG032990 , U01 AG046139 , R01 AG018023 , U01 AG006576 , U01 AG006786 , R01 AG025711 , R01 AG017216 , and R01 AG003949 ; National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820 ; the CurePSP Foundation ; and support from Mayo Foundation . Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke ( U24 NS072026 , National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the NIA ( P30 AG19610 , Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002 , Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001 , 0011 , 05-901 , and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research . Mount Sinai Brain Bank (MSBB) data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt of the Mount Sinai School of Medicine through funding from NIA grant U01AG046170 . Furthermore, Emory study data were supported through funding from NIA grants P50 AG025688 , U01 AG046161 , and U01 AG061357 . This study was also supported in part by grants from the NIH ( R01AG053960 , R01AG050631 , R01AG057339 , U01AG046161 , U01 AG046139 , RF1AG054014 , RF1 AG057440 , R01AG057473 , R01AG057914 , P50 NS38377 , and F31AG050357 ). C.G.M. was supported by the Cullen Foundation and the Baylor College of Medicine Medical Scientist Training Program (MSTP). J.M.S. was additionally supported by grants from the Huffington Foundation , the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital , and a Career Award for Medical Scientists from the Burroughs Wellcome Fund . Z.L. received additional support from the National Science Foundation , Division of Mathematical Sciences ( DMS-1263932 ), the Cancer Prevention Research Institute of Texas ( RP170387 ), the Houston Endowment , and the Neurodegeneration Consortium and Belfer Family Foundation . T.M.D. is supported by the JPB Foundation and is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation of the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with the Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the foundation’s Parkinson’s Disease Program ( M-2014 ). We are grateful to Dr. Bruce Yankner for contributing additional mouse RNA-seq data. This study is part of the NIA AMP-AD, MODEL-AD, and Resilience-AD programs. Publisher Copyright: © 2020 The Authors
PY - 2020/7/14
Y1 - 2020/7/14
N2 - We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
AB - We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
KW - Alzheimer's disease
KW - RNA-seq
KW - aging
KW - coexpression analysis
KW - differential expression analysis
KW - meta-analysis
KW - mouse models
KW - neuroinflammation
KW - transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85087814633&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087814633&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.107908
DO - 10.1016/j.celrep.2020.107908
M3 - Article
AN - SCOPUS:85087814633
VL - 32
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 2
M1 - 107908
ER -