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PMID: 35288716 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Integrating whole-genome sequencing with multi-omic data reveals the impact of structural variants on gene regulation in the human brain.

Nature neuroscience ·Vol. 25 ·No. 4 ·2022-00-00 ·Pages 504-514

Vialle RA, de Paiva Lopes K, Bennett DA, Crary JF, Raj T

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.

MeSH Terms
Brain Genome, Human Genomic Structural Variation Humans Middle Aged Quantitative Trait Loci/genetics Reproducibility of Results Whole Genome Sequencing
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Vialle Ricardo A ORCID
Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
de Paiva Lopes Katia ORCID
Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Bennett David A
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Crary John F
Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Raj Towfique ORCID
Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/s41593-022-01031-7
Email
[email protected]
Published
2022-00-00
Epub
2022-00-14
Pages
504-514
Language
English
Region
United States
NLM ID
9809671
PMCID
PMC9245608
Subset
IM
Grants
NIA NIH HHS · U01 AG046152 · United States
NIA NIH HHS · R01 AG054005 · United States
NIA NIH HHS · P50 AG016574 · United States
NIA NIH HHS · R01 AG017917 · United States
NIH HHS · S10 OD026880 · United States
NIA NIH HHS · P30 AG010161 · United States
NIA NIH HHS · R01 AG032990 · United States
NINDS NIH HHS · R01 NS080820 · United States
NIA NIH HHS · RF1 AG065926 · United States
NIA NIH HHS · P01 AG017216 · United States
NIA NIH HHS · R01 AG018023 · United States
NIA NIH HHS · R01 AG054008 · United States
NIA NIH HHS · P30 AG072975 · United States
NIA NIH HHS · U01 AG061356 · United States
NIA NIH HHS · R56 AG055824 · United States
NIA NIH HHS · U01 AG032984 · United States
NIA NIH HHS · R01 AG030146 · United States
NIA NIH HHS · U01 AG046170 · United States
NIA NIH HHS · U01 AG068880 · United States
NIA NIH HHS · U01 AG046139 · United States
NIA NIH HHS · P01 AG003949 · United States
NINDS NIH HHS · U24 NS072026 · United States
NIA NIH HHS · P30 AG019610 · United States
NIA NIH HHS · P50 AG025711 · United States
NIA NIH HHS · U01 AG006786 · United States
NIA NIH HHS · R01 AG036836 · United States
NIA NIH HHS · R01 AG015819 · United States
External Links
PubMed source DOI: 10.1038/s41593-022-01031-7 PMC Full Text View journal details
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