Abstract
Structural variants (SVs), which are genomic rearrangements of more than 50 base pairs, are an important source of genetic diversity and have been linked to many diseases. However, it remains unclear how they modulate human brain function and disease risk. Here we report 170,996 SVs discovered using 1,760 short-read whole genomes from aged adults and individuals with Alzheimer’s disease. By applying quantitative trait locus (SV-xQTL) analyses, we quantified the impact of cis-acting SVs on histone modifications, gene expression, splicing and protein abundance in postmortem brain tissues. More than 3,200 SVs were associated with at least one molecular phenotype. We found reproducibility of 65–99% SV-eQTLs across cohorts and brain regions. SV associations with mRNA and proteins shared the same direction of effect in more than 87% of SV–gene pairs. Mediation analysis showed ~8% of SV-eQTLs mediated by histone acetylation and ~11% by splicing. Additionally, associations of SVs with progressive supranuclear palsy identified previously known and novel SVs.
| Original language | English |
|---|---|
| Pages (from-to) | 504-514 |
| Number of pages | 11 |
| Journal | Nature Neuroscience |
| Volume | 25 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2022 |
Access to Document
Fingerprint
Dive into the research topics of 'Integrating whole-genome sequencing with multi-omic data reveals the impact of structural variants on gene regulation in the human brain'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature Neuroscience, Vol. 25, No. 4, 04.2022, p. 504-514.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Integrating whole-genome sequencing with multi-omic data reveals the impact of structural variants on gene regulation in the human brain
AU - Vialle, Ricardo A.
AU - de Paiva Lopes, Katia
AU - Bennett, David A.
AU - Crary, John F.
AU - Raj, Towfique
N1 - Funding Information: We thank the participants of AMP-AD cohorts for their essential contributions and gift to these projects. ROS/MAP study data were provided by the Rush Alzheimer’s Disease Center at Rush University Medical Center. Data collection was supported through funding by National Institute on Aging (NIA) grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152 and U01AG61356 and by the Illinois Department of Public Health. Mayo RNA-seq study data were provided by the following sources: the Mayo Clinic Alzheimer’s Disease Genetic Studies, led by N. Ertekin-Taner and S. 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; by National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820; by the CurePSP Foundation; and by support from the 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 NINDS (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 data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt of the Mount Sinai School of Medicine through funding from NIA grant U01AG046170. The authors thank B. Zhang and E. Wang for assistance with data sharing and members of the Raj and Crary laboratories for their feedback on the manuscript. We thank J. Humphrey for insightful comments and suggestions during this work. This work was supported by grants from the National Institutes of Health (NIH) (NIH NIA U01-AG068880, NIA R01-AG054005, NIA R56-AG055824 and NIA R01-AG054008). This work was supported, in part, through the computational and data resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. We thank the Mount Sinai Technology Development core for help and support with performing long-read sequencing. Cartoons in Figs. 1 and 5b,c were created with BioRender. The research reported in this paper was supported by the Office of Research Infrastructure of the NIH under award number S10OD026880. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: We thank the participants of AMP-AD cohorts for their essential contributions and gift to these projects. ROS/MAP study data were provided by the Rush Alzheimer’s Disease Center at Rush University Medical Center. Data collection was supported through funding by National Institute on Aging (NIA) grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152 and U01AG61356 and by the Illinois Department of Public Health. Mayo RNA-seq study data were provided by the following sources: the Mayo Clinic Alzheimer’s Disease Genetic Studies, led by N. Ertekin-Taner and S. 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; by National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820; by the CurePSP Foundation; and by support from the 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 NINDS (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 data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt of the Mount Sinai School of Medicine through funding from NIA grant U01AG046170. The authors thank B. Zhang and E. Wang for assistance with data sharing and members of the Raj and Crary laboratories for their feedback on the manuscript. We thank J. Humphrey for insightful comments and suggestions during this work. This work was supported by grants from the National Institutes of Health (NIH) (NIH NIA U01-AG068880, NIA R01-AG054005, NIA R56-AG055824 and NIA R01-AG054008). This work was supported, in part, through the computational and data resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. We thank the Mount Sinai Technology Development core for help and support with performing long-read sequencing. Cartoons in Figs. and were created with BioRender. The research reported in this paper was supported by the Office of Research Infrastructure of the NIH under award number S10OD026880. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/4
Y1 - 2022/4
N2 - Structural variants (SVs), which are genomic rearrangements of more than 50 base pairs, are an important source of genetic diversity and have been linked to many diseases. However, it remains unclear how they modulate human brain function and disease risk. Here we report 170,996 SVs discovered using 1,760 short-read whole genomes from aged adults and individuals with Alzheimer’s disease. By applying quantitative trait locus (SV-xQTL) analyses, we quantified the impact of cis-acting SVs on histone modifications, gene expression, splicing and protein abundance in postmortem brain tissues. More than 3,200 SVs were associated with at least one molecular phenotype. We found reproducibility of 65–99% SV-eQTLs across cohorts and brain regions. SV associations with mRNA and proteins shared the same direction of effect in more than 87% of SV–gene pairs. Mediation analysis showed ~8% of SV-eQTLs mediated by histone acetylation and ~11% by splicing. Additionally, associations of SVs with progressive supranuclear palsy identified previously known and novel SVs.
AB - Structural variants (SVs), which are genomic rearrangements of more than 50 base pairs, are an important source of genetic diversity and have been linked to many diseases. However, it remains unclear how they modulate human brain function and disease risk. Here we report 170,996 SVs discovered using 1,760 short-read whole genomes from aged adults and individuals with Alzheimer’s disease. By applying quantitative trait locus (SV-xQTL) analyses, we quantified the impact of cis-acting SVs on histone modifications, gene expression, splicing and protein abundance in postmortem brain tissues. More than 3,200 SVs were associated with at least one molecular phenotype. We found reproducibility of 65–99% SV-eQTLs across cohorts and brain regions. SV associations with mRNA and proteins shared the same direction of effect in more than 87% of SV–gene pairs. Mediation analysis showed ~8% of SV-eQTLs mediated by histone acetylation and ~11% by splicing. Additionally, associations of SVs with progressive supranuclear palsy identified previously known and novel SVs.
UR - http://www.scopus.com/inward/record.url?scp=85126242404&partnerID=8YFLogxK
U2 - 10.1038/s41593-022-01031-7
DO - 10.1038/s41593-022-01031-7
M3 - Article
C2 - 35288716
AN - SCOPUS:85126242404
SN - 1097-6256
VL - 25
SP - 504
EP - 514
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 4
ER -