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Allele-Specific Expression and High-Throughput Reporter Assay Reveal Functional Variants in Human Brains with Alcohol Use Disorders

Authors :
Jay A. Tischfield
Xiaoling Xuei
Xi Rao
Andy B. Chen
Yunlong Liu
Sean P. Farris
Tatiana Foroud
Hai Lin
Mayfield Rd
Joseph Ipe
Howard J. Edenberg
Alison Goate
Jill L. Reiter
Manav Kapoor
Todd C. Skaar
Kriti S. Thapa
Hongyu Gao
Katherine A. Hargreaves
Hongmei Gu
Dongbing Lai
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with alcohol use disorder (AUDs) may cause expression differences, we integrated deep RNA-seq and genome-wide association studies (GWAS) data from four postmortem brain regions of 30 AUDs subjects and 30 controls (social/non-drinkers) and analyzed allele-specific expression (ASE). We identified 90 genes with differential ASE in subjects with AUDs compared to controls. Of these, 61 genes contained 437 single nucleotide polymorphisms (SNPs) in the 3’ untranslated regions (3’UTR) with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that showed affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these are in binding sites of miRNAs and RNA binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....fd4ecb0fa417fb77b71d7a44017f959f
Full Text :
https://doi.org/10.1101/514992