Browsing by Author "Slesinger, Paul A."

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    5. Collaborative Study on the Genetics of Alcoholism: Functional genomics
    (Wiley, 2023) 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.; Medical and Molecular Genetics, School of Medicine
    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.
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    Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons
    (Springer Nature, 2023) Popova, Dina; Gameiro-Ros, Isabel; Youssef, Mark M.; Zalamea, Petronio; Morris, Ayeshia D.; Prytkova, Iya; Jadali, Azadeh; Kwan, Kelvin Y.; Kamarajan, Chella; Salvatore, Jessica E.; Xuei, Xiaoling; Chorlian, David B.; Porjesz, Bernice; Kuperman, Samuel; Dick, Danielle M.; Goate, Alison; Edenberg, Howard J.; Tischfield, Jay A.; Pang, Zhiping P.; Slesinger, Paul A.; Hart, Ronald P.; Medical and Molecular Genetics, School of Medicine
    Synonymous and noncoding single nucleotide polymorphisms (SNPs) in the KCNJ6 gene, encoding G protein-gated inwardly rectifying potassium channel subunit 2 (GIRK2), have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects with KCNJ6 variants ("Affected: AF") and four control subjects without variants ("Unaffected: UN"). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single-cell RNA sequencing suggests that KCNJ6 AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude that KCNJ6 variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.
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    The collaborative study on the genetics of alcoholism: Genetics
    (Wiley, 2023) Johnson, Emma C.; Salvatore, Jessica E.; Lai, Dongbing; Merikangas, Alison K.; Nurnberger, John I.; Tischfield, Jay A.; Xuei, Xiaoling; Kamarajan, Chella; Wetherill, Leah; COGA Collaborators; Rice, John P.; Kramer, John R.; Kuperman, Samuel; Foroud, Tatiana; Slesinger, Paul A.; Goate, Alison M.; Porjesz, Bernice; Dick, Danielle M.; Edenberg, Howard J.; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.
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    Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons
    (Society for Neuroscience, 2024-04-17) Prytkova, Iya; Liu, Yiyuan; Fernando, Michael; Gameiro-Ros, Isabel; Popova, Dina; Kamarajan, Chella; Xuei, Xiaoling; Chorlian, David B.; Edenberg, Howard J.; Tischfield, Jay A.; Porjesz, Bernice; Pang, Zhiping P.; Hart, Ronald P.; Goate, Alison; Slesinger, Paul A.; Medical and Molecular Genetics, School of Medicine
    Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the KCNJ6 gene. KCNJ6 encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating KCNJ6 using an isogenic approach with human glutamatergic neurons derived from induced pluripotent stem cells (male and female donors). Using multielectrode arrays, population calcium imaging, single-cell patch-clamp electrophysiology, and mitochondrial stress tests, we find that elevated GIRK2 acts in concert with 7–21 d of ethanol exposure to inhibit neuronal activity, to counteract ethanol-induced increases in glutamate response, and to promote an increase intrinsic excitability. Furthermore, elevated GIRK2 prevented ethanol-induced changes in basal and activity-dependent mitochondrial respiration. These data support a role for GIRK2 in mitigating the effects of ethanol and a previously unknown connection to mitochondrial function in human glutamatergic neurons.