# GABRA2 genetic variants and chromosome conformation in induced pluripotent stem cell-derived neural cells

> **NIH NIH F30** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $50,520

## Abstract

Project Summary
Alcohol use disorders (AUDs) affect approximately 8.5% of the United States population. Risk of developing
an AUD is influenced by both genetic and environmental factors, with heritability estimated to be between 50
and 60%. While several genetic variants have been associated with increased risk of developing an AUD, little
is known about the biological mechanisms linking such variants to the pathophysiology of AUD. One of the
most commonly-examined single-nucleotide polymorphisms (SNPs) associated with increased genetic risk of
developing an AUD is rs279858, a synonymous SNP located in exon 5 of GABRA2. This tag-SNP serves as a
bookmark for a 140 kilobase (kb) haplotype block containing a number of SNPs that are in high linkage
disequilibrium (LD) and are associated with increased genetic risk for developing an AUD. The absence of a
linked coding variant suggests that AUD-associated risk in this region due to an unidentified functional non-
coding variant that influences developmentally-regulated gene expression of GABRA2 or nearby genes. Using
induced pluripotent stem cell (iPSC)-derived neurons, it has been reported that decreased expression of
GABRA2 on chromosome 4p12 as well as that of the GABRA4 and GABRB1 subunit genes 500kb distal to
GABRA2 is correlated with the rs279858 risk C-allele, as compared to iPSC-derived neurons that are
homozygous for the non-risk-associated allele. Furthermore, promoter methylation analysis suggests that in
CC lines, long-range intrachromosomal interactions may bring enhancer elements into close physical proximity
to GABRA2 and subsequently alter the transcription of the chr4p12 GABA gene cluster, as compared to a
more-localized mechanism of transcriptional control in TT homozygotes. The goal of this project is to define
the elements of the long-range interactions that appear to influence transcription from this region, to better
understand the proximal genetic effects of this AUD-associated variation and thereby stimulate further
understanding of how it may relate to risk of developing AUD.

## Key facts

- **NIH application ID:** 9976412
- **Project number:** 5F30AA027153-03
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Alexandra Marie Goetjen
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976412

## Citation

> US National Institutes of Health, RePORTER application 9976412, GABRA2 genetic variants and chromosome conformation in induced pluripotent stem cell-derived neural cells (5F30AA027153-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976412. Licensed CC0.

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