Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans

Abstract

As with other genetically complex common psychiatric and medical conditions, multiple genetic and environmental components contribute to alcohol use disorders (AUDs), which can confound attempts to identify genetic components. Intermediate phenotypes are often more closely correlated with underlying biology and have often proven invaluable in genetic studies. Level of response (LR) to alcohol is an intermediate phenotype for AUDs, and individuals with a low LR are at increased risk. A high rate of concurrent alcohol and nicotine use and dependence suggests that these conditions may share biochemical and genetic mechanisms. Genetic association studies indicate that a genetic locus, which includes the CHRNA5-CHRNA3-CHRNB4 gene cluster, plays a role in nicotine consumption and dependence. Genetic association with alcohol dependence was also recently shown. We show here that two of the markers from the nicotine studies also show an association (multiple testing corrected P < 0.025) with several LR phenotypes in a sample of 367 siblings. Additional markers in the region were analyzed and shown to be located in a 250-kb expanse of high linkage disequilibrium containing three additional genes. These findings indicate that LR intermediate phenotypes have utility in genetic approaches to AUDs and will prove valuable in the identification of other genetic loci conferring susceptibility to AUDs.alcohol use disorders ͉ genetics ͉ quantitative trait locus M ultiple genetic and environmental components contribute to alcohol use disorders (AUDs) (1). As with other genetically complex common psychiatric and medical conditions, it is challenging to match genetic variants with the disease phenotype. Intermediate phenotypes, such as the large numbers of colon polyps seen in the familial polyposis form of colon cancer (2), are often closer to the underlying biology and may provide a better phenotype for genetic analysis (3).The level of response (LR) to alcohol has been developed as an intermediate phenotype for AUDs (4). Physical responses (e.g., body sway) and subjective feelings (as measured on the Subjective High Assessment Scale [SHAS]) show reproducible individual variation among subjects. Prospective studies have shown that individuals with a low LR are at increased risk for AUDs (5). Alcohol LR is heritable, on a par with alcohol dependence, with genes explaining 40% to 60% of the variance (6-8). Linkage analyses have shown interesting but inconclusive findings (9-11).Frequent concurrence of alcohol and nicotine use and dependence suggests a shared etiology (12). Twin studies (13-16) conclude there are shared genetic factors that influence alcohol and nicotine consumption and dependence. Functional evidence that nicotinic receptors are involved in alcohol responses is provided by studies showing that mice treated with the smoking cessation drug varenicline, a nicotinic receptor partial agonist, have an attenuated response to alcohol; they drink less and show reduced levels of reinstatement following alcohol abstinence (17)....

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…Further evidence for a possible shared genetics background is supplied by Joslyn et al 95 who reported association of several SNPs in the chromosomal region of CHRNA5-CHRNA3-CHRNB4 locus (particularly rs1051730 and rs8034191) with alcohol level of response, which is considered an intermediate phenotype for alcohol addiction. 95 Age at initiation of both tobacco use and alcohol drinking was significantly associated with three other SNPs within the CHRNA5ÀCHRNA3ÀCHRNB4 locus (rs8023462, rs1948, rs514743) in a US sample of 1075 individuals of diverse ethnicity.…”

“…95 Age at initiation of both tobacco use and alcohol drinking was significantly associated with three other SNPs within the CHRNA5ÀCHRNA3ÀCHRNB4 locus (rs8023462, rs1948, rs514743) in a US sample of 1075 individuals of diverse ethnicity. rs8023462 and rs1948 significantly predicted early age of initiation for tobacco with a hazard ratio of 1.35 for the TT genotype of rs8023462 and a hazard ratio of 1.29 for the CC genotype of rs1948.…”

Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine

“…In humans, certain single-nucleotide polymorphisms within this gene cluster represent risk alleles for nicotine dependence (Berrettini and Doyle, 2012), whereas other polymorphisms may influence alcohol-related behaviors (Choquet et al, 2013;Hallfors et al, 2013;Joslyn et al, 2008;Wang et al, 2009). In rodents, α5-, α3-, and β4-containing nAChRs influence the rewarding and aversive properties of nicotine (Fowler et al, 2011;Morel et al, 2013) and the symptoms accompanying its withdrawal (Jackson et al, 2013;Salas et al, 2004;Salas et al, 2009).…”

A Brief History of Research on the Genetics of Alcohol and Other Drug Use Disorders

“…LR can be measured through direct observations of the response to alcohol at a given blood alcohol concentration or through a retrospective questionnaire; LR can be documented very early in a person's drinking career; it predicts later heavy drinking and alcohol problems but not SUDs; and is itself 40%-60% genetic (Chung and Martin, 2009;Quinn and Fromme, 2011;Schuckit and Smith, 2013;Schuckit et al, 2012b). Studies have described the association of this lower sensitivity to alcohol with a variation in an alcohol-metabolizing enzyme active in the brain, CYP2E1 (Webb et al, 2011), a gene that affects how potassium channels in cells respond to alcohol (KCMNA1), variations in the gene for the protein that affects how the brain transports the chemical serotonin back into cells (SLC6A4), as well as additional gene variations from the cholinergic receptor complex on chromosome 15 (Choquet et al, 2013;Joslyn et al, 2008;Schuckit et al, 2001Schuckit et al, , 2005Wilhelmsen et al, 2003). The effects on heavier drinking for genes that contribute to the low LR operate partly through several environmental events (e.g., drinking in peers and reactions to stress), and the underlying mechanism may relate to a mild ineffi ciency in the amount of brain effort required to process some cognitive tasks (Paulus et al, 2012).…”