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

Nat Neurosci. 2022 Apr;25(4):504-514. doi: 10.1038/s41593-022-01031-7. Epub 2022 Mar 14.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain
  • Genome, Human
  • Genomic Structural Variation*
  • Humans
  • Middle Aged
  • Quantitative Trait Loci* / genetics
  • Reproducibility of Results
  • Whole Genome Sequencing