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Etiology of Alcohol Use Disorder: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Vladimir Vladimirov.

Alcohol use disorder (AUD) is a complex, chronic, debilitating condition impacting millions worldwide. Genetic, environmental, and epigenetic factors are known to contribute to the development of AUD. Long non-coding RNAs (lncRNAs) are a class of regulatory RNAs, commonly referred to as the “dark matter” of the genome, with little to no protein-coding potential. LncRNAs have been implicated in numerous processes critical for cell survival, suggesting that they play important functional roles in regulating different cell processes. LncRNAs were also shown to display higher tissue specificity than protein-coding genes and have a higher abundance in the brain and central nervous system, demonstrating a possible role in the etiology of psychiatric disorders.

  • long non-coding RNA
  • neuropsychiatric disorders
  • alcohol use disorder

1. The RNA World

The completion of the human genome project in 2003 demonstrated a greater need to understand the role of non-coding regions in the classical definition of genes [1]. Approximately 80% of the human genome is biochemically active [2]. The Encyclopedia of DNA Elements (ENCODE) Consortium found that 76% of the genome’s DNA is transcribed into RNA, with only 2% of the transcribed RNA translated into functional proteins [2][3] (Figure 1). The remaining 98% are not translated, and these RNA are known as non-coding RNAs (ncRNAs), also commonly referred to as “junk” or “dark matter” of the genome [4][5]. Based on their genomic organization, ncRNA can be classified into two main classes: long ncRNA and short ncRNA, with the long ncRNA further classified into regulatory or structural ncRNA [6]. Regulatory ncRNA is also delineated into small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs) [6][7],. which are the focus of this review. We Researchers point the reader to several excellent reviews on sncRNAs, such as microRNA (miRNA), a shorter non-coding RNA, approximately 22 nucleotides in length, [8][9] upon additional interest. LncRNAs are greater than 200 nucleotides in length, transcribed by RNA polymerase II, and have little to no protein-coding abilities due to a lack of open reading frames (ORF) [10]. LncRNAs have a similar genomic organization to the protein-coding genes, i.e., they can be 5’ capped, have exon/intron structure, and can be polyadenylated. LncRNAs can interact with other proteins involved in histone modification processes and chromatin remodeling [11]. Numerous types of lncRNAs exist with distinct functional roles in biogenesis, structure, or activity in the cell [6]. Compared to protein-coding genes, lncRNAs generally have lower expression rates; however, they display higher tissue specificity with an abundance in the brain and central nervous system, suggesting a connection to the etiology of psychiatric disorders and the emergence of behavioral phenotypes [10].
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Figure 1. Schematic classification of the human transcriptome: 76% of protein-coding genes from the human genome (blue circle) are transcribed into RNA (gray circle), whereas only 2% (red circle) are translated into functional proteins. The remaining 98% are known as non-coding RNA. Two sub-classes emerge from non-coding RNA: small non-coding RNA (sncRNA) and long non-coding RNAs (lncRNAs).
The first lncRNA, H19, was serendipitously discovered in the 1980s after applying differential hybridization screening of cDNA libraries of mice [12][13]. Originally classified as mRNA, H19 ultimately was classified into a novel group, non-coding RNA, due to an absence of translation [13]. A surge of discoveries in the non-coding RNA world throughout the 1990s later piqued interest in understanding the roles and abundance of the novel class.

2. lncRNA Functions

Like protein-coding genes, lncRNAs can be transcribed from either the sense or antisense strand of DNA [10]. LncRNAs exhibit a wide variety of cellular and molecular functions, depending on their subcellular localization; however, there is no universally agreed-upon classification system. Accounting for functional overlap, 11 distinct species of lncRNAs have been described, which are summarized in Figure 1. Among these, the four most discussed categories of lncRNAs in the literature are (i) long intergenic (lincRNA), (ii) antisense, (iii) sense intronic, and (iv) bidirectional lncRNAs (Figure 2) [14][15]. LincRNAs are located between protein-coding genes, whereas the antisense lncRNAs overlap one or more exons on the opposite strand of mRNA, and sense lncRNAs overlap one or more exons on the same mRNA strand. Bidirectional lncRNAs are transcribed from the promoter of a protein-coding gene in the opposite direction [15][16].
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Figure 2. The four most common categories of lncRNAs: (I) long intergenic ncRNA (lincRNA), (II) antisense lncRNA, (III) sense intronic ncRNA, and (IV) bidirectional lncRNA.
LncRNAs have numerous functions inside and outside the nucleus (Figure 3). In the nucleus, they participate in chromatin architecture and remodeling (e.g., chromatin organization and stabilization) [17], transcriptional regulation of protein-coding genes [18], facilitation of protein–protein interaction [18], and function as a sponge through competitive endogenous RNAs (ceRNAs) [19]. CeRNAs, also known as endogenous sponges, use microRNA response elements (MREs) to crosstalk between miRNAs and lncRNAs to act as a decoy to influence gene expression levels. Approximately 54% of lncRNAs are detected in the cytoplasm [20]. MREs target lncRNA transcripts to post-transcriptionally regulate gene expression via transcript degradation or translation inhibition. Other lncRNAs have been featured in numerous pathological functions such as mRNA stabilization, sequestration of MREs aided by miRNA, stimulation of apoptosis, and assisting in alternative splicing (Figure 3) [21][22][23]. LncRNAs are also shown to be essential to chromatin architecture. For example, the X-inactive-specific transcript (Xist), a well-known lncRNA, stabilizes the silenced X-chromosome during early embryonic development [24]. Xist, as well as other lncRNAs such as Airn and Kcnq1ot1, create a cascade of events causing Polycomb repression complexes (PRCs) to modify chromatin structure over broad regions of the genome [25]. An antisense lncRNA, HOTAIR, binds to PRC2 to promote histone H3 and lysine 27 methylation along with lysine 4 demethylation, which contributes to pathogenesis of various neurological diseases, such as major depressive disorder or cancers, such as breast cancer [26][27][28].
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Figure 3. Molecular and pathological mechanisms of lncRNAs in and outside the nucleus: Various functions of lncRNAs occur, such as histone modification, transcriptional regulation, scaffolding, microRNA sequestration, splicing, and protein–protein interaction. Adapted from Hu et al. 2018 and Yang et al. 2021. Created using BioRender.
Considering their biological functions, not surprisingly, many lncRNAs have been implicated in multiple facets of human health and disease, such as cancer biology, diabetes, and fatty liver disease [29][30][31][32][33]. Due to their high expression in the brain, lncRNAs were also implicated in the neuropathology of psychiatric disorders. For example, two lncRNAs, GOMAFU and NEAT2/MALAT1, have been known to affect mRNA splicing of genes previously shown to be associated with schizophrenia [34]. GOMAFU affects the splicesome by directly binding to splicing factor 1 for disrupted-in-schizophrenia-1 (DISC1) and v-erb-a-erythroblastic leukemia viral oncogene homolog 4 (ERBB4), two genes that play roles in the splicesome and were shown to contribute to schizophrenia [35]. Upon dysregulation, GOMAFU interferes with the expression of splice factor proteins, leading to alternative splicing patterns to genes such as DISC1 and ERBB4 [34][35]. GOMAFU is highly enriched in neurons and facilitates neuronal regulation and support through interacting with serine/arginine-rich splicing factors during growth and development. GOMAFU also promotes neuronal differentiation during development [36]. NEAT1, PCAT1, RMRP, and NKILA are lncRNAs associated with neuropsychiatric phenotypes such as major depressive disorder (MDD), addictive behavior, and substance abuse [37][38]. NEAT1 was shown to act as a regulatory lncRNA that reduces the expression of HTT, thereby contributing to Huntington’s disease, and once again shows the broad implications that lncRNAs have on human health and diseases related to the brain [39][40].

3. Epidemiology of AUD

Alcohol use disorder (AUD) is a debilitating condition impacting millions of individuals worldwide. In the United States, the average 12-month and lifetime prevalence of AUD is 13.9% and 29.1%, respectively, with males historically having a higher prevalence (i.e., 17.6% and 36.0%) than females (i.e., 10.4% and 22.7%) [41]. An annual average of 87,798 alcohol-attributable deaths (AAD) and 2.5 million years of potential life lost (YPLL) occurred from 2006 through 2010, with similar numbers still occurring over a decade later [42]. The transition from DSM-IV to DSM-5 led to merging alcohol addiction and alcohol dependence into a single AUD diagnosis [43]. A person meeting any 2 of the 11 DSM-5 criteria during the same 12-month period would receive a diagnosis of AUD [44], with the severity of AUD—mild, moderate, or severe—based on the number of criteria met. Examples of criteria include craving for alcohol, neglect of day-to-day activities, difficulty in cutting down on drinking, and failure to fulfill major obligations due to excessive drinking (Table 1). However, integrating these separate diagnoses into one disorder, AUD, poses a challenge to future studies that utilize data obtained prior to DSM-5 implementation. Therefore, it is vital to confirm the new AUD diagnosis through access to patient records. Caution must also be taken to ensure AUD is not used interchangeably with alcohol abuse and alcohol dependency. Some of the studies mentioned below (e.g., Van Booven et al. 2021) disclose whether the patients’ diagnosis is based on DSM-IV or DSM-5 to ensure consistency between different studies utilizing DSM-IV or DSM-5 diagnostic criteria [45]. Future metastudies may also consider merging multiple datasets that represent both DSM-4 and DSM-5. AUD is also highly comorbid, i.e., it has been associated with other substance abuse disorders, major depressive disorder (MDD), and anxiety disorders [41]. Approximately 1 in 5 patients with lifetime AUD will be treated, indicating a strong need to understand genetic and environmental factors contributing to predispositions for acquiring AUD.
Table 1. DSM-5 symptoms for Alcohol Use Disorder (AUD. The presence of 2 or more of these 11 listed symptoms indicates Alcohol Use Disorder (AUD) [43]. Levels of severity are classified as Mild: 2–3 symptoms, Moderate: 4–5 symptoms, and Severe: 6 or more symptoms. Modified from the DSM-5 questionnaire given to patients [43].
DSM-5 Alcohol Use Disorder Symptoms
1 Drinking longer or more than intended
2 Tried to quit or decrease levels of drinking, but failed
3 Sick from the aftereffects
4 Incapability to not think about drinking
5 Drinking interferes with your daily life (job, family, school, etc…)
6 Continued drinking habits regardless of daily life struggles
7 Loss of pleasure in things you once loved
8 Reckless behavior (driving, fighting, unsafe sex, etc…)
9 Continued drinking even if depressed or anxious or experiencing memory problems
10 Increased tolerance to alcohol
11 Withdrawal symptoms (shakiness, nausea, sweating, etc…)

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