Epigenomic mapping and effect sizes of noncoding variants associated with psychotropic drug response

Pharmacogenomics
Gerald A HigginsBrian D Athey

Abstract

To provide insight into potential regulatory mechanisms of gene expression underlying addiction, analgesia, psychotropic drug response and adverse drug events, genome-wide association studies searching for variants associated with these phenotypes has been undertaken with limited success. We undertook analysis of these results with the aim of applying epigenetic knowledge to aid variant discovery and interpretation. We applied conditional imputation to results from 26 genome-wide association studies and three candidate gene-association studies. The analysis workflow included data from chromatin conformation capture, chromatin state annotation, DNase I hypersensitivity, hypomethylation, anatomical localization and biochronicity. We also made use of chromatin state data from the epigenome roadmap, transcription factor-binding data, spatial maps from published Hi-C datasets and 'guilt by association' methods. We identified 31 pharmacoepigenomic SNPs from a total of 2024 variants in linkage disequilibrium with lead SNPs, of which only 6% were coding variants. Interrogation of chromatin state using our workflow and the epigenome roadmap showed agreement on 34 of 35 tissue assignments to regulatory elements including enhancers and pr...Continue Reading

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Citations

Sep 5, 2015·Pharmacogenomics·Gerald A HigginsBrian D Athey
Aug 28, 2016·Biochimica Et Biophysica Acta. General Subjects·Nick Plant
Apr 8, 2017·Methods : a Companion to Methods in Enzymology·Gerald A HigginsBrian D Athey
Apr 27, 2018·Pharmacogenomics·Alexandr A KalininBrian D Athey
May 8, 2018·PloS One·Rosario Lopez-RodriguezAntonio Gonzalez
Nov 24, 2018·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Hamid M AbdolmalekySam Thiagalingam
Sep 19, 2019·Pharmacological Reviews·Gerald A HigginsBrian D Athey
Aug 3, 2019·Bioinformatics·Sierra S NishizakiAlan P Boyle

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Methods Mentioned

BETA
Hi-C
DNA-seq
genotyping
RNA-Seq
sequence-based predictions

Software Mentioned

Segway
GBR
Ensembl genome bowser
Roadmap EpiGenome
WUSTL Genome Browser
UCSC Genome Browser
HaploSeq
GeneVar
RegulomeDB
Roadmap EpiGenome Browser

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