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GENETIC of ADDICTION: COMMON and UNCOMMON FACTORS Giada Juli1 & Luigi Juli2 1Catanzaro, Italy 2Mental Health Department, Catanzaro, Italy

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GENETIC of ADDICTION: COMMON and UNCOMMON FACTORS Giada Juli1 & Luigi Juli2 1Catanzaro, Italy 2Mental Health Department, Catanzaro, Italy Psychiatria Danubina, 2015; Vol. 27, Suppl. 1, pp 383–390 Conference paper © Medicinska naklada - Zagreb, Croatia GENETIC OF ADDICTION: COMMON AND UNCOMMON FACTORS Giada Juli1 & Luigi Juli2 1Catanzaro, Italy 2Mental Health Department, Catanzaro, Italy SUMMARY Epidemiological studies strongly suggest that genetic factors operate at all steps of addictions, including vulnerability to initiation, continued use, and propensity to become dependent. Several studies have been popular to investigate the relative contributions of genetic and environmental factors, including the availability of and exposure to a substance, and shared and unique environments. The genetic influence on addiction has proved to be substantial, and heritabilities for most addictive disorders are moderate to high. In this work we evaluate the current status of data that analyzed genetic contribution in addictions. Key words: addictions- genetic factors-dependence * * * * * INTRODUCTION have analyzed alcohol addiction (or alcohol depen- dence) but the genetic influence have been evaluated Addiction is characterized by a compulsion to take a also for the susceptibility of tobacco addiction (or substance, with goal-directed behavior toward excessive dependence), cannabis, opioids and other psychoactive substance intake and a loss of control in limiting intake. substances. The aim of this review is to summarize the Recently, the Addictive Disorders have been enri- available literature that underly common and un- ched not only by synthetic substances of use/abuse, but common factors in genetic of addictions. also by behaviors capable to promote psychopatho- logical states which are disabling and serious. In fact, ALCOHOL DEPENDENCE (AD) apart from alcohol, tobacco, cocaine, cannabis, heroin and other substances, science has identified new addic- It is known that alcohol dependence (AD) can be tions such as Eating Disorders (Juli 2014), Gambling considered as a familiar trait with well characterized Addiction, Internet and Sex Addiction. genetic factors of susceptibility that are not dependent Why do some people become addicted to one or of environment influence. more substances while other people do not? Twin Studies in adopted sons have revealed a major studies estimated that more than 50% of the responsi- incidence of AD in individuals of which the biological bility is due to genetic factors. In the analysis of risk parents were alcoholism-affected (but were not the factors for addictions, it is important to understand the adoptive parents) comparing to individuals of which biological phenomena that are responsible of these adoptive parents were alcoholism-affected (but were not behaviors and to develop drugs that can interfere with the biological parents). It is considered that genetics the molecular mechanisms to prevent and to treat the contributes to alcoholism for about 50% for men and addictions. 25% for women (Reich 1998). The genetic influence for addictions is not due to a It has been shown that a family history of alcoholism contribution of a single gene but it is the result of the (FH) constitutes a major risk factor for the development interaction of different genes that together with environ- of alcohol use disorders (Conway 2003). A number of ment factors, induce a condition of “susceptibility” to neurobiological and behavioral differences have been the disorder. In particular, studing the genetics of identified between youth who are family history addiction, has been considered the genetic variables that positive (FH+) for alcoholism and family history are normally present among people and are defined negative (FH−) peers, including increased impulsivity polymorphisms. These variables become risk factors (Gierski 2013) and differences in recruitment of when are present together with particular environment regulatory brain regions during inhibitory demands, as factors (culture, environmental position, substances revealed by functional magnetic resonance imaging availability) and other biological factors of suscep- (fMRI) (DeVito 2013, Hardee 2014). Recently, Cohen- tibility. It seems that the heritability of addictions is not Gilbert et al., using magnetic resonance spectroscopy well defined but it is possible to inherit the suscep- (MRS), investigated the glutamatergic system, including tibility to these behaviors and this can be related to turnover of the general metabolic pool, as indexed by genetic variables of the neurotransmission system. the ratio of glutamine (Gln) to glutamate (Glu) in FH− Human genetic studies such as linkage and associations and FH+ adolescents and emerging adults; relationships studies (Juli 2012) have been performed to analyze the between Gln/Glu and impulsivity were also examined in genetic influence on addictions. Most of the studies these populations (Cohen-Gilbert 2015). Levels of Gln S383 Giada Juli & Luigi Juli: GENETIC OF ADDICTION: COMMON AND UNCOMMON FACTORS Psychiatria Danubina, 2015; Vol. 27, Suppl. 1, pp 383–390 and Glu are of particular interest in alcohol research the behavioral consequences of alcohol (Crabbe 2008) because of alcohol use, dependence, and withdrawal have and other drugs (Buck 2001). The specific genes and been shown to be associated with both acute and alleles may differ from those associated in humans, but protracted alterations in glutamatergic systems (Hermann overall, animal models have confirmed and extended 2012, Krystal 2003). Positive associations between findings of GABA's involvement in AD and other Gln/Glu, FH+ status and impulsivity were identified for addictions. However, the molecular mechanism of the both adolescent and emerging adult groups. In summary, effects of GABA are being established by microarray elevated Gln/Glu that together with family history status analysis (Ponomarev 2006). may confer risk for substance use disorders in adoles- Data from meta-analysis suggest different candidate cents. This neurobiological vulnerability may manifest genes that are associated with alcohol dependence such behaviorally as reduced cognitive control, which may as 5-Hydroxytryptamine transporter (5HTT/SERT) enhance risk-taking during adolescence, but dissipates (Feinn 2005), cytochrome P450 family 2 subfamily A by early adulthood, possibly due to maturation of the polypeptide 6 (CYP2A6) (Munafo 2004), dopamine prefrontal cortex (Cohen-Gilbert 2015). In addition, transporter (DAT1) (Stapleton 2007), dopamine recep- FH+ individuals have been reported to display altered tor 2 (DRD2) (Munafo 2007), Interleukin-10 (IL10) subjective responses to NMDA receptor antagonists, (Marcos 2008) and brain-derived neurotrophic factor such as ketamine, relative to FH− counterparts, sugge- (BDNF) (Gratacos 2007). sting an important role for NMDA in the genetic vulnerability to alcoholism and substance abuse NICOTINE DEPENDENCE (ND) (Petrakis 2004). Numerous large twin studies for alcohol-related It has been estimated that for nicotine dependence behaviors have consistently shown that heritability of the contribution of genetics is around 28%-84%. alcohol abuse and dependence ranges from 50% to 70% Meta-analysis of the twin studies shows that both (Agrawal 2008). genes and environment are important in smoking-related Linkage studies have identified a locus on chromo- behaviors, with an estimated mean heritability of 50% some 4q near the aldehyde dehydrogenase (ADH) gene for smoking initiation and 59% for nicotine dependence cluster as a major locus for alcoholism in American (ND). Genetic factors have a larger role in initiation Indians and Caucasians (Long 1998, Reich 1998, than in persistence in women, whereas the opposite is Saccone 2000), in addition to the known ADH2 and observed in men (Li 2003, Madden 1999). aldehyde dehydrogenase 2 (ALDH2) variants in Nicotine exerts its biological function by binding to Asians and Jewish Americans (Osier 2002, Shea 2001, nicotinic acetylcholine receptors (nAChRs), which are Higuchi 1996). The ADH locus contains a cluster of composed of five subunits. There are 12 nAChR seven genes, of which ADH2 is the most important subunit genes: nine alpha (α2–α10) and three beta (β2– across populations, although functional variants in β4) subunits. Several variants of these genes have been ADH4 and ADH7 might also be involved (Edenberg associated with dependence on nicotine, alcohol, and 2006, Osier 2004). cocaine (Li 2009). For instance, a significant asso- Several studies identificated the gamma-aminobu- ciation of variants in CHRNA4, which encodes the α4 tyric acid A receptor subunit 2 (GABRA2) as a suscep- subunit, with ND has been observed in three inde- tibility factor for alcoholism. Early linkage studies in pendent studies: the first study revealed significant Southwest American Indians, implicated chromosome protective effects of two single nucleotide polymor- 4p near the GABRA2/B1 cluster (Long 1998); these phisms (SNPs) against ND in Chinese men (Feng results were confirmed in some Caucasian studies 2004); a second study showed that four SNPs are (Zinn-Justin 1999) and became particularly convincing significantly associated with ND in European and when linkage of alcohol-related phenotypes was combi- African Americans, but the effects differed as a ned with a statistical study of the genetic loci that function of ethnicity or sex (Li 2005); the third one contribute to variations in a quantitative trait data reported that two SNPs are significantly associated (Porjesz 2002). For this reason, the GABRA2 is now with the subjective response to smoking (Hutchison
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