Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? PMC

Efforts also are underway to develop a wearable alcohol sensor that can provide objective measures of alcohol consumption by patients in real time for use in clinical trials (Litten et al., 2010). One such device, the Secure Continuous Remote Alcohol Monitor (or SCRAM), developed by Alcohol Monitoring Systems Inc. (AMS), measures alcohol intake in real time and is currently being used in the criminal justice system (Litten et al., 2010). NIAAA is currently supporting several projects to improve wearable alcohol sensors, making them more precise in measuring alcohol intake, less expensive, and more comfortable to wear. Finally, to advance our understanding of individual neurons involved in mental and addictive disorders, a conductive polymer mesh is being developed that can be implanted into the brain to study the in-vivo action of each cell. This approach could prove to be an important tool for discovering new targets for medications development (Fletcher, 2015).

Epigenetic studies of AUD have emerged as an important avenue for understanding the complex interplay among genetics, environment, and gene regulation in the development and progression of AUD. Epigenetic factors include transcription factors, noncoding RNAs, DNA modifications, or histone modifications that alter the gene expression and consequently affect phenotypes, without changing the DNA sequence (121, 122). While epigenetic status is highly heritable and affected by environmental factors, including alcohol exposures, certain epigenetic changes in specific brain regions have been implicated in the etiology of AUD (123). Genetic correlation of problematic alcohol use, cannabis use disorder, cocaine dependence, opioid use disorder, and nicotine dependence with psychiatric disorders, behavioural traits, and other complex phenotypes. The 95% confidence interval of the genetic correlation estimates were obtained from previous studies13, 37, 44, 48, 185 that applied the linkage disequilibrium score regression method.

7. Medications acting on neuroendocrine pathways: Oxytocin, ABT-436, PF-5190457

(b) Some studies have endeavored to include samples in multiple ancestries (55, 56, 63, 64, 75, 80), but the sample sizes in the non-European ancestries are smaller than sample sizes in the European ancestries — a common issue in human genetic studies (53, 54). With more multiancestral biobanks becoming available, including MVP, the Global Biobank Meta-analysis Initiative (93), and the All of Us Research Program (94), we anticipate that the gap in diversity will diminish. Funding agencies should also direct attention to studies that propose recruitment focused on non-European ancestry participants. Current studies are using single nucleus RNA sequencing and ATAC‐sequencing to measure gene expression and chromatin accessibility in many different types of cells within the brain (unpublished data). Because different cell types differ in gene expression, these studies should give us a much clearer understanding of functional differences between individuals with and without AUD.

• Several recent GWAS have used this approach, and it is now common to study quantitative measures, including alcohol consumption and aspects of disordered drinking, in large population samples.
• Developing collaborative networks and partnerships will provide more opportunities and choices for advancing alcohol medications development.
• In particular, CYP2A6 is involved in two key reactions, nicotine oxidation to nicotine iminium ion, and cotinine oxidation to hydroxycotinine.
• Making pharmaceutical companies aware of the importance of AUD and its potential as a therapeutic area has been challenging.

Recent discoveries on the molecular genetics of alcohol use behaviors

Mazumdar and Eberhart addressed the genetic factors influencing susceptibility to ethanol-induced birth defects, focusing on the role of nicotinamide nucleotide transhydrogenase (Nnt) in mitigating oxidative stress. This study, conducted in zebrafish embryos, demonstrated that ethanol exposure leads to increased apoptosis and craniofacial malformations in Nnt mutants due to elevated reactive oxygen species. To further explore the mechanisms underlying PAE-induced oxidative stress, Darbinian et al. examined mitochondrial DNA (mtDNA) in fetal brain tissues from PAE-exposed rats and humans, as well as fetal brain-derived exosomes (FB-Es) obtained from maternal blood.

Although recent research has expanded understanding of alcohol use disorder, more research is needed to identify the neurobiological, genetic and epigenetic, psychological, social, and environmental factors most critical in the etiology and treatment of this disease. Implementation of this knowledge in clinical practice and training of health care providers is also needed to ensure appropriate diagnosis and treatment of individuals suffering from alcohol use disorder. A candidate-locus postmortem brain analysis showed that prodynorphin is downregulated in the dorsolateral prefrontal cortex of individuals with a diagnosis of AD or alcohol abuse when compared to controls149. The investigators hypothesized that prodynorphin down-regulation could lead to neurotransmission disinhibition, which could contribute to the formation of alcohol-related behaviour149. The cerebral cortex transcriptome-wide profile of AUD showed a lack of overlap with the gene expression changes observed in other psychiatric disorders (i.e., autism, schizophrenia, bipolar disorder, and depression)150. In nucleus accumbens, subjects with AD showed transcriptomic downregulation of gene modules enriched for neuronal-specific marker genes and upregulation of gene modules enriched for astrocyte and microglial specific marker genes151.

Genes and environment: how they contribute to SUDs

Getting a group of subjects exposed to a psychoactive drug without progression to SUD is not difficult for commonly used substances like nicotine and alcohol. If unexposed subjects are used as controls for such studies, then any differences in marker frequency factors between the SUD and control groups reflects some mixture of genetic effects on both initiation and dependence given initiation. This CCC model has been most extensively applied to smoking and nicotine dependence27 and more recently to cannabis28,29. The genetic risk for smoking initiation is more highly correlated with the genetic risk for progression to nicotine dependence than many neurobiologists might think. Furthermore, shared environment (for example, rates of smoking in peers) typically affects smoking initiation but not the progression from initiation to dependence. and medical models of treatment for alcohol use disorder, as well as the development of new pharmacological and behavioral treatment options.}

IDENTIFYING MECHANISMS OF AUD‐ASSOCIATED SNPs IN HUMAN NEURON MODELS

In 2009, the first GWAS of AUD was conducted in a German sample comprising 487 cases of AUD and 1,358 population-based controls; no variants reached the genome-wide significant (GWS) threshold (44). In 2011, the same team augmented the sample size by recruiting more participants and identified a variant located between ADH1B and ADH1C. In 2010, a study of Dutch and Australian samples was the first AUD GWAS to apply imputation for missing SNPs using the HapMap reference panel (46). The study reported no GWS results for AUD, but three SNPs were identified for comorbid AUD and nicotine dependence (47). No association was identified in a general community sample in Australia, but this study discussed the polygenic nature of AUD and projected the need for larger sample size (48).

Furthermore, the shared genetic risk for substance use and related behaviors indicates that GxI studies that assess a range of substances may better align with etiological theories (Glantz & Leshner, 2000; Kendler et al., 2003; Mayes & Suchman, 2015; Vanyukov et al., 2003, 2012). Future research that focuses on GxI effects in the prevention/intervention of marijuana and other illicit substances, in addition to alcohol, may more comprehensively address the problem of substance use and related harms. SUDs are classic complex traits with strong evidence supporting the etiological roles of both genetic or biological and environmental or social risk factors.

Long-term exposure to alcohol causes adaptive changes in several neurotransmitters, including GABA, glutamate, and norepinephrine, among many others. Discontinuation of alcohol ingestion results in the nervous system hyperactivity and dysfunction that characterizes alcohol withdrawal (15, 16). Acting on several types of brain receptors, glutamate represents one of the most common excitatory neurotransmitters. As one of the major inhibitory neurotransmitters, GABA plays a key role in the neurochemical mechanisms involved in intoxication, tolerance, and withdrawal. This brief review can offer only a very simplified overview of the complex neurobiological basis of alcohol use disorder. For deeper, more detailed analysis of this specific topic, the reader is encouraged to consult other reviews (15, 16).

Purpose of review:

The inherently different function of rodent and human BBB (Aday et al., 2016) accounts for some of the failed CNS therapeutic trials (Alavijeh et al., 2005) as well as being implicated in neurodegenerative and psychiatric diseases (Desai et al., 2007; Saito and Ihara, 2014). These more complex hiPSC-derived cultures provide an important approach for modeling disease specific circuitry and recent advances in genetic studies of alcohol use disorders pmc drug delivery. In other risk pathways, it remains unclear whether common comorbidities with major depression, conduct disorder and antisocial personality disorder are due to direct etiological overlap between the conditions.

U.S. Food and Drug Administration–approved pharmacological treatments

• In addition to Kcnq genes, a number of other K+ channel SNPs (Table 1) and transcriptome changes (Table 2) in human alcoholics and preclinical models have been reported that present unique opportunities for the development of small molecules to target these channels.
• Reducing the stigma of alcohol use disorder and moving toward a public health approach to addressing this problem may further increase the range of acceptable treatment options.
• Moreover, only 46 percent of new CNS compounds succeed in pivotal clinical trials, compared with 66 percent for non-CNS compounds (Kaitin and Milne, 2011).
• There is currently a long way to go in understanding DDs and with this second Special Issue, we aimed to compile recent advances, considering different levels of approach that provide interesting data, with a view to being transferred as soon as possible to health care.

Nonetheless, transient, asymptomatic hepatic transaminase elevations have also been observed in some clinical trials and in the postmarketing period; therefore, naltrexone should be used with caution in patients with active liver disease and should not be used in patients with acute hepatitis or liver failure. In this review, we describe how COGA has been conducting cellular and molecular studies to understand functional mechanisms linking genes and variants identified by GWAS to the risk for AUD. These include studies on gene regulation in lymphoblastoid cells from COGA participants with and without alcohol exposure, and in post‐mortem brain tissues from individuals with or without AUD, combined with bioinformatic analyses (Figure 1). Molecular studies also use high throughput reporter assays (HTRA) to identify SNPs in which alternate alleles differ in driving gene expression. To evaluate variants with hypothesized function in the central nervous system (CNS), electrophysiology and gene expression studies are performed in neurons differentiated from induced pluripotent stem cells (iPSCs) derived from COGA participants (Figure 1).

However, because of the lack of efficacy of a-2 agonists and β-blockers in preventing severe alcohol withdrawal syndrome and the risk of masking withdrawal symptoms, these drugs are recommended not as monotherapy, but only as a possible adjunctive treatment. (a) Different definitions of AUD and proxy phenotypes (e.g., AUDIT-P) have shared genetic architecture, resulting in improved power in gene discovery when they are combined from different cohorts (78, 80). Deep phenotyping (either using same definition or focusing on subphenotypes) in larger cohorts could reduce the phenotypic heterogeneity and increase the possibility of identifying trait-specific associations and pathways (92). In summary, clinical studies conducted in the past two years provide preliminary support of NMDA receptor antagonism (ifenprodil), but not agonism (glycine), in AUD treatment.