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

By Xi Rao, Kriti S Thapa, Andy B Chen, Hai Lin, Hongyu Gao, Jill L Reiter, Katherine A Hargreaves, Joseph Ipe, Dongbing Lai, Xiaoling Xuei, Hongmei Gu, Manav Kapoor, Sean P Farris, Jay Tischfield, Tatiana Foroud, Alison Goate, Todd C Skaar, R. Dayne Mayfield, Howard Edenberg, Yunlong Liu

Posted 09 Jan 2019
bioRxiv DOI: 10.1101/514992

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 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.

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