Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease
Abstract Background Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive. Methods To elucid...
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2016-11-01
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Series: | Genome Medicine |
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Online Access: | http://link.springer.com/article/10.1186/s13073-016-0355-3 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Minghui Wang Panos Roussos Andrew McKenzie Xianxiao Zhou Yuji Kajiwara Kristen J. Brennand Gabriele C. De Luca John F. Crary Patrizia Casaccia Joseph D. Buxbaum Michelle Ehrlich Sam Gandy Alison Goate Pavel Katsel Eric Schadt Vahram Haroutunian Bin Zhang |
spellingShingle |
Minghui Wang Panos Roussos Andrew McKenzie Xianxiao Zhou Yuji Kajiwara Kristen J. Brennand Gabriele C. De Luca John F. Crary Patrizia Casaccia Joseph D. Buxbaum Michelle Ehrlich Sam Gandy Alison Goate Pavel Katsel Eric Schadt Vahram Haroutunian Bin Zhang Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease Genome Medicine Alzheimer’s disease Dementia Differential expression Gene co-expression network Gene module Systems biology |
author_facet |
Minghui Wang Panos Roussos Andrew McKenzie Xianxiao Zhou Yuji Kajiwara Kristen J. Brennand Gabriele C. De Luca John F. Crary Patrizia Casaccia Joseph D. Buxbaum Michelle Ehrlich Sam Gandy Alison Goate Pavel Katsel Eric Schadt Vahram Haroutunian Bin Zhang |
author_sort |
Minghui Wang |
title |
Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease |
title_short |
Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease |
title_full |
Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease |
title_fullStr |
Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease |
title_full_unstemmed |
Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease |
title_sort |
integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to alzheimer’s disease |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2016-11-01 |
description |
Abstract Background Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive. Methods To elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits. Results The neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities. Conclusions This transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD. |
topic |
Alzheimer’s disease Dementia Differential expression Gene co-expression network Gene module Systems biology |
url |
http://link.springer.com/article/10.1186/s13073-016-0355-3 |
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doaj-6f5c9ccb12a04ff398d143576bc62ad42020-11-24T21:39:00ZengBMCGenome Medicine1756-994X2016-11-018112110.1186/s13073-016-0355-3Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s diseaseMinghui Wang0Panos Roussos1Andrew McKenzie2Xianxiao Zhou3Yuji Kajiwara4Kristen J. Brennand5Gabriele C. De Luca6John F. Crary7Patrizia Casaccia8Joseph D. Buxbaum9Michelle Ehrlich10Sam Gandy11Alison Goate12Pavel Katsel13Eric Schadt14Vahram Haroutunian15Bin Zhang16Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDivision of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDivision of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceNuffield Department of Clinical Neurosciences, University of OxfordFriedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDivision of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDepartment of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L Levy PlacePsychiatry, JJ Peters VA Medical CenterDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDivision of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDivision of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceAbstract Background Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive. Methods To elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits. Results The neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities. Conclusions This transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD.http://link.springer.com/article/10.1186/s13073-016-0355-3Alzheimer’s diseaseDementiaDifferential expressionGene co-expression networkGene moduleSystems biology |