5. Collaborative Study on the Genetics of Alcoholism: Functional genomics.
paper
Primary
Public
- Authors
- Gameiro-Ros, Isabel; Popova, Dina; Prytkova, Iya; Pang, Zhiping P; Liu, Yunlong; Dick, Danielle; Bucholz, Kathleen K; Agrawal, Arpana; Porjesz, Bernice; Goate, Alison M; Xuei, Xiaoling; Kamarajan, Chella; COGA Collaborators; Tischfield, Jay A; Edenberg, Howard J; Slesinger, Paul A; Hart, Ronald P
- Year
- 2023
- Journal
- Genes, brain, and behavior
- PMID
- 37533187
- DOI
- 10.1111/gbb.12855
- PMCID
- PMC10550792
Alcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.
Summary of functional genomics strategies in COGA. COGA uses brain post‐mortem tissue and lymphoblastoid cells from healthy (unaffected) and AUD‐diagnosed (affected) COGA participants to study gene expression and its regulation by different sequencing strategies. Novel high throughput reporter assays such as PASSPORT‐seq are applied to analyze genetic variants in which alternate alleles differ in driving gene expression. In parallel, COGA uses iPSCs derived from AUD affected and unaffected COGA participants and differentiates them into neurons. Genetically‐defined human neurons allow evaluation of the functional consequences of AUD‐associated variants with hypothesized effects in the central nervous system using transcriptomic and electrophysiological approaches. Isogenic iPSC‐based strategies are used to model and functionally evaluate specific AUD‐associated SNPs. Created with BioRender.com.
PASSPORT‐seq assay for differential expression of alleles in 3′ untranslated regions. (A) PASSPORT‐seq vector. 51 bp segments with the SNP to be tested in position 26 are inserted into the 3′ untranslated region of the luciferase gene. After transfecting human cells with pools of these constructs, RNA and DNA are extracted from the pooled cells and the amount of RNA expressed from each is compared with the amount of DNA. (B–E) Results of PASSPORT‐seq assays. The number of unique reads of DNA and RNA from six replicate transfections of two different cell types is plotted, with alternate alleles on Y axis and reference alleles on X axis; on the left are the allele frequencies in the RNA (R) and DNA (D). (B, C) Effects of rs151371 variant in SH‐SY5Y cells and HMC3 cells, respectively; both alleles showed biased allele expression. (D, E) Effects of rs2306124 in SH‐SY5Y cells and HMC3 cells, respectively; this SNP demonstrated biased allele expression in HMC3 cells but not in SH‐SY5Y cells.
Functional consequences of non‐synonymous SNPs in OPRM1. (A) Acute ethanol application causes an increase in the inhibitory tone (spontaneous inhibitory postsynaptic currents, iPSCs) in iPSC‐derived inhibitory human neurons carrying N40 major allele. (B) Chronic ethanol treatment increases GABAergic transmission in inhibitory human neurons carrying D40 minor allele. Modified from Scarnati et al. 38
Functional consequences of a non‐coding SNPs in KCNJ6. (A) Manhattan plot showing genome‐wide association of frontal theta event‐related oscillation with several SNPs, including a synonymous SNP, rs702859, in the KCNJ6 gene on chromosome 21. (B) KCNJ6 SNPs influence the magnitude and topography of ERO theta power during reward processing in a monetary gambling task. (C) Impact of KCNJ6 haplotype (multiple linked SNPs) on iPSC‐derived excitatory neurons: (i) GIRK2 expression is decreased in the affected individuals (AUD/KCNJ6 minor alleles) as measured by puncta counts; (ii) neuronal excitability is increased in the affected individuals (AUD/KCNJ6 minor alleles) as measured by number of induced action potentials. Modified from Kang et al., 55 Kamarajan et al., 57 and Popova et al. 39
Ethanol‐mediated responses in a context of non‐coding SNPs in KCNJ6. (A) Chronic ethanol induces GIRK2 expression in iPSC‐derived excitatory human neurons. (B) Chronic ethanol eliminates differences in GIRK2 expression and excitability between affected (AUD/KCNJ6 minor alleles) and unaffected (not AUD/KCNJ6 major alleles) iPSC‐derived neurons. (C) KCNJ6 overexpression mimics chronic ethanol responses. Modified from Popova et al. 39
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Pleiotropic Effects of <i>Grm7</i>/<i>GRM7</i> in Shaping Neurodevelopmental Pathways and the Neural Substrate of Complex Behaviors and Disorders. | Gyetvai BM et al. | — | 2025 | → |
| Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model. | Li X et al. | — | 2024 | → |
| 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics. | Gameiro-Ros I et al. | — | 2023 | → |
| Collaborative study on the genetics of alcoholism: The strength of collaboration, team science, and longitudinal data. | Ehringer MA | — | 2023 | → |