GENETICS OFALCOHOL USE DISORDER
Contrary to the stigmatizing perception, alcohol dependence is not a mark of moral decay, but the result of combining environmental, social, cultural and especially biological factors, family studies finding that about 50% of the risk is due to heredity. Genetic linkage and association studies have failed to identify significant risk alleles, except for the alcohol-metabolizing enzyme genes. Thus, a new approach was needed - genome wide association studies (GWAS) that do not depend on a pre-existing hypothesis and highlighted new polymorphisms associated with susceptibility to alcoholism. A review of family, twin, linkage, candidate genes and GWAS will be briefly presented.
According to the World Health Organization
(WHO), harmful alcohol consumption is responsible for 5.9% of the global mortality, with a 3-4 times higher risk of premature death for alcoholics compared to the general population. The association with behavioral and psychiatric disorders is well known, alcohol dependence has become one of the most important public health problems through its social and economic impact and strong functional and quality of life impairment, even at a young age. (1)
It is estimated that in developed countries, up to 80% of male and 60% of female adults use alcohol at some time in their lives, the prevalence of dependence for men reaching, according to some studies, even 10%. (2)
Current diagnostic criteria, established by the International Classification of Diseases, 10th edition (ICD-10) and the Diagnostic and Statistical Manual of Mental
Disorders, 5th edition (DSM-5), do not match perfectly on this topic. If DSM-IV-TR describes two distinct disorders, alcohol abuse and dependence, DSM-5 integrates these two entities into a single one Alcohol Use Disorder (AUD). (3) At the more severe end of the spectrum, the dependence implies tolerance, withdrawal, loss of control, compulsion („craving”) to drink daily or almost daily, despite s i g n i f i c a n t d i s a b i l i t y. T h e d i s o r d e r m a y b e underdiagnosed, some studies revealing that only a quarter of addicts receive treatment. (4) By applying DSM-5 criteria, in the US, 36% of men and 22.7% of women develop AUD during their lifetime, in the younger population, gender differences have narrowed. (5)
In the “Alcohol related disorders” chapter, ICD- 10 differentiates between harmful use (assuming physical or mental impairment) and alcohol dependence, that requires three out of six positive criteria: strong desire or compulsion to drink, difficulties in avoiding initial use, in discontinuing and controlling the consumed quantity, withdrawal or alcohol use to avoid its symptoms, tolerance, neglecting other activities / interests to obtain, use or recover after consumption, continued use despite physical, psychological or cognitive problems. (6)
Besides several types of genetic studies, another argument for the role of genetics in the development of alcoholism are laboratory animals genetically manipulated to present features such as the preference for alcohol, sensitivity to the sedative effects or withdrawal symptoms. (7)
FAMILYAND TWIN STUDIES
Cognitive tests applied during functional MRI revealed inappropriate activation of long neural pathways that connect temporo-parietal regions to prefrontal areas. These brain disturbances occur in families with a strong history of alcohol dependence, supporting a biological basis, genetically determined. The impairment of cognitive functions and work memory required to resolve conflicts generates the disinhibited, even antisocial behavior. (8)
Twin studies report that 50-70% of the risk of developing an AUD is given by genetic factors. The strongest association was with the reducing risk genotype, the allele ALDH2 * 2 (the gene encoding the m i t o c h o n d r i a l h e p a t i c e n z y m e a l d e h y d e dehydrogenase).The polymorphism, common in Asians, but rare in Europeans, leads to altered alcohol metabolism with the development of facial erythema, tachycardia, sweating and gastrointestinal symptoms, creating aversion. (9)
The COGA study (Collaborative Study on the Genetics of Alcoholism) identified regions of interest on chromosomes 1, 2, 10, 13. (10) Depending on the components of alcoholism, regions on chromosomes 1 and 11 were associated with the initial response to alcohol, the age of onset with areas on chromosome 9, while a maximum alcohol use, with regions on chromosomes 12 and 18. Signals from the chromosomes 1, 6 and 22 were correlated with tolerance, while the severity of the withdrawal was linked to a region on chromosome 2. (11)Likewise, regions encoding the structure of the Gamma-Aminobutyric Acid Type A Receptor, Alpha2 Subunit (GABRA2), located on chromosome 4 were correlated with addictions in general.(12) In the same way, the muscarinic acetylcholine M2 (CHRM2) genes, located on chromosome 7q were found to affect cognitive functions, depressive symptoms and the development of alcohol dependence.(13, 14)
ASSOCIATION (CANDIDATE GENE) STUDIES Association studies, that test candidate genes in regions discovered through linkage studies, confirmed the protective effect of Alcohol Dehydrogenase 1B (Class I), Beta Polypeptide alleles ADH1B*2 (found in Asian populations) and ADH1B*3 (more specific for African Americans) and also of the Alcohol Dehydrogenase 1C (Class I), Gamma Polypeptide allele ADH1C*2, which stimulates the metabolism of alcohol to acetaldehyde. A similar lower risk of dependence was associated with the Aldehyde Dehydrogenase 2 Family (Mitochondrial) a l l e l e , A L D H 2 * 2 ( t h a t h a m p e r s a c e t a l d e h y d e metabolism). (15)
Most of the known neurotransmitters play a role in the development of addiction. The polymorphism of the Ankyrin Repeat And Kinase Domain Containing 1 of the D2 dopamine receptor (DRD2/ANKK1), involved in reward pathways that activates pleasure-generating behaviors (consumption of carbohydrates and fats, sexual activity) and also the survival instinct, was correlated with alcohol preference. (16)
Polymorphisms of the genes encoding type A GABA receptor (GABRA2, the most widespread class of cerebral inhibitory receptors that influences the subjective response to ethanol) and of the type B GABA receptor correlate with alcohol dependence. (17,18). Other studies refute the relationship between GABAergic system genes and alcoholism, limiting it only to specific situations such as poly substance abuse or a particularly strong family history. (19)
Neuropeptide Y gene (NPY), with the G1258A single nucleotide polymorphism (SNP) and the NPY Pro7 allele modulates risk of alcohol dependence in the central amygdala by translating negative emotional states in anxiety generated behavior. (20,21,22). In the same way, the polymorphism of the corticotropin releasing factor 1 receptor gene (CRF1-R) influences the anxious phenotype that leads to excessive ethanol consumption. (23)
In the cholinergic system, the beta 2 subunit of the nicotinic cholinergic receptor (CHRNB2) was associated with the response to alcohol and nicotine. (24)
Imaging studies and animal models support the involvement of serotonin receptor and transporter. Alcohol and nicotine co-dependence, but also attention- deficit hyperactivity disorder (ADHD) appear to be influenced by genetic variants of the Importin 11 region of the 5-Hydroxytryptamine Receptor 1A (IPO11-HTR1A). (25, 26) Changes in the presynaptic 1B serotonin autoreceptor gene may determine the susceptibility to alcohol dependence, and also to cocaine and heroin abuse, some studies suggesting that the polymorphisms HTR1B A-161 could represent a genetic marker for alcoholism. (27, 28)
The gene for the serotonin receptor 4 (HTR4), located in the limbic system, specifically in the hippocampus, involved in the development of depression by generating anhedonia, could have a role in the pathogenesis of alcohol dependence. (29, 30) The polymorphism of the Solute Carrier Family 6 Member 4 gene promoter region (SLC6A4), on chromosome 17, encoding the serotonin transporter, has been evaluated in multiple studies regarding its association with alcohol dependence, but a meta-analysis concluded that this relationship does not exist. (31) On the other hand, in the case of alcoholism comorbid with depression, homozygous carriers of the S allele of the serotonin-transporter-linked polymorphic region (5HTTLPR) have an increased risk. (32)
Lastly, glutamatergic system genes seem to play a role in addiction development. Thus the N-methyl-D- aspartate (NMDA) subunit of the glutamate receptor 2B (Glu2B) is overexpressed in the hippocampus after chronic exposure to ethanol. (33) SNPs of the metabotropic glutamate receptor 3 gene (GRM3) modulates the prefrontal cortex activity in alcoholic patients, influencing the executive functions. (34) GENOME WIDE ASSOCIATION STUDIES (GWAS)
Genome-Wide Association Studies (GWAS) conducted on samples of thousands of alcohol addicted patients, is a more recent approach, different from genetic linkage studies, which can discover unknown alleles involved in the development of a certain pathology. The criterion for statistical significance in this type of study is very restrictive (p5x10-8), so only a few genes have been reported to be associated with alcoholism. Unlike association studies, GWAS do not require the involvement of a particular gene hypothesis that should be tested. (34).
GWAS does not search for a specific gene, instead millions of SNPs across the entire genome are analysed. The first positive study of this kind on alcoholism was published in 2009 by Treutlein et al, that identified two new loci on chromosome 2q35, near the gene for the peroxisomal trans-2-enozil-CoA reductase (PECR, the key enzyme of fatty acid metabolism, correlated with depression and with P300 response amplitude, related to decision making). (35, 36)
Most GWAS have identified risk polymorphisms of ADH and ALDH genes, others, which studied the comorbidity with nicotine addiction, frequently associated, found SNPs near the Microtubule Affinity Regulating Kinase 1 gene (MARK1, that influences the migration of neurons in the hippocampus) and near the diethylazodicarboxylate Bis(oxazoline) helicase 6 (DEAD-Box Helicase 6, DDX6, involved in cell development and differentiation). (37, 38, 39)
Chen et al. revealed that the ankyrin repeat domain-containing protein 7 gene located on chromosome 7q31 (ANKRD7, which influence the functioning of the cerebellum) and cytokine-like1 gene on chromosome 14p16 (CYTL1, correlated with bipolar disorder and schizophrenia) could play an important role in risk developing alcohol dependence. (40)
WHOLE GENOME SEQUENCING
Genomics is constantly developing techniques for sequencing the entire genome, with the cheaper version of the whole exome sequencing (WES) becoming increasingly more affordable. In this way, rare recessive mutations can be identified in exonic regions (areas that encode proteins). These techniques found point mutations in autism spectrum, affective and psychotic disorders, so favorable results in connection to addiction could be expected. (41)
GWAS – Genome Wide Association Studies
WHO – World Health Organization
ICD-10 – International Classification of Diseases, 10th edition
DSM – Diagnostic and Statistical Manual of Mental Disorders
AUD – Alcohol Use Disorder
ALDH – aldehyde dehydrogenase
COGA – Collaborative Study on the Genetics of Alcoholism
GABRA2 – Gamma-Aminobutyric Acid Type A Receptor Alpha2 Subunit
CHRM2 – Cholinergic Receptor Muscarinic 2
ADH1B – Alcohol Dehydrogenase 1B (Class I), Beta Polypeptide
ADH1C – Alcohol Dehydrogenase 1C (Class I), Gamma Polypeptide
ALDH2 – Aldehyde Dehydrogenase 2 Family (Mitochondrial)
DRD2/ANKK1 – Ankyrin Repeat And Kinase Domain Containing 1 of the D2 dopamine receptor
NPY – Neuropeptide Y
SNP – Single Nucleotide Polymorphism
CRF1-R – Corticotropin Releasing actor 1 Receptor
CHRNB2 – Cholinergic Receptor Nicotinic Beta 2 Subunit
ADHD – attention-deficit hyperactivity disorder
IPO11-HTR1A – Importin 11 region of the 5- Hydroxytryptamine Receptor 1A
HTR1B A – 5-Hydroxytryptamine Receptor 1B HTR4 – 5-Hydroxytryptamine Receptor 4
SLC6A4 – Solute Carrier Family 6 Member 4
5HTTLPR – Serotonin-transporter-linked polymorphic region
NMDA – N-methyl-D-aspartate
Glu2B – Glutamate Receptor 2B
GRM3 – Glutamate Metabotropic Receptor 3
PECR – Peroxisomal Trans-2-Enoyl-CoA Reductase
MARK1 – Microtubule Affinity Regulating Kinase 1
DDX6 – DEAD-Box Helicase 6 (diethylazodicarboxylate Bis(oxazoline) helicase 6)
ANKRD7 – Ankyrin Repeat Domain 7
CYTL1 – Cytokine Like 1
WES – Whole Exome Sequencing
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