A glutamatergic network mediates lithium response in bipolar disorder as defined by epigenome pathway analysis

Pharmacogenomics
Gerald A HigginsBrian D Athey

Abstract

A regulatory network in the human brain mediating lithium response in bipolar patients was revealed by analysis of functional SNPs from genome-wide association studies (GWAS) and published gene association studies, followed by epigenome mapping. An initial set of 23,312 SNPs in linkage disequilibrium with lead SNPs, and sub-threshold GWAS SNPs rescued by pathway analysis, were studied in the same populations. These were assessed using our workflow and annotation by the epigenome roadmap consortium. Twenty-seven percent of 802 SNPs that were associated with lithium response (13 published studies gene association studies and two GWAS) were shared in common with 1281 SNPs from 18 GWAS examining psychiatric disorders and adverse events associated with lithium treatment. Nineteen SNPs were annotated as active regulatory elements such as enhancers and promoters in a tissue-specific manner. They were located within noncoding regions of ten genes: ANK3, ARNTL, CACNA1C, CACNG2, CDKN1A, CREB1, GRIA2, GSK3B, NR1D1 and SLC1A2. Following gene set enrichment and pathway analysis, these genes were found to be significantly associated (p = 10(-27); Fisher exact test) with an AMPA2 glutamate receptor network in human brain. Our workflow results...Continue Reading

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Citations

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
Jan 18, 2017·The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry·Pierre A GeoffroyCynthia Marie-Claire
Apr 27, 2018·Pharmacogenomics·Alexandr A KalininBrian D Athey
Apr 24, 2020·Current Topics in Medicinal Chemistry·Darby J E LoweTony P George
Dec 14, 2017·International Journal of Molecular Sciences·Eunsoo Won, Yong-Ku Kim
May 24, 2018·Molecular Diagnosis & Therapy·Claudia PisanuAlessio Squassina
Sep 19, 2019·Pharmacological Reviews·Gerald A HigginsBrian D Athey
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Jan 26, 2021·Psychiatric Genetics·Delfina JaniriGabriele Sani
Apr 4, 2021·Pharmaceuticals·Courtney M VeceraRodrigo Machado-Vieira
May 27, 2021·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Claudia PisanuAlessio Squassina
Sep 5, 2015·Pharmacogenomics·Gerald A HigginsBrian D Athey

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Methods Mentioned

BETA
RNA-seq
genotyping

Software Mentioned

Panther
WUSTL epigenome browser
Ingenuity Pathway Analysis
IPA
Google Scholar
pathway commons
ChromImpute
ChromHMM
HaploReg
Hi

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