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Nat Neurosci. 2017 Oct;20(10):1418-1426. doi: 10.1038/nn.4632. Epub 2017 Sep 4.

An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome.

Author information

1
Departments of Statistics and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
2
Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
3
Broad Institute, Cambridge, Massachusetts, USA.
4
Center for Translational &Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, USA.
5
Sage Bionetworks, Seattle, Washington, USA.
6
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
7
Canadian Institute for Advanced Research, CIFAR Program in Child and Brain Development, Toronto, Ontario Canada.

Abstract

We report a multi-omic resource generated by applying quantitative trait locus (xQTL) analyses to RNA sequence, DNA methylation and histone acetylation data from the dorsolateral prefrontal cortex of 411 older adults who have all three data types. We identify SNPs significantly associated with gene expression, DNA methylation and histone modification levels. Many of these SNPs influence multiple molecular features, and we demonstrate that SNP effects on RNA expression are fully mediated by epigenetic features in 9% of these loci. Further, we illustrate the utility of our new resource, xQTL Serve, by using it to prioritize the cell type(s) most affected by an xQTL. We also reanalyze published genome wide association studies using an xQTL-weighted analysis approach and identify 18 new schizophrenia and 2 new bipolar susceptibility variants, which is more than double the number of loci that can be discovered with a larger blood-based expression eQTL resource.

PMID:
28869584
PMCID:
PMC5785926
DOI:
10.1038/nn.4632
[Indexed for MEDLINE]
Free PMC Article

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