Host-parasite interaction associated with major mental illness.

Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.

Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Psychopathy, PCL-R, and MAOA genotype as predictors of violent reconvictions.

The Revised Psychopathy Checklist (PCL-R) has shown a moderate association with violence. The efficacy of PCL-R in varying monoamine oxidase A (MAOA) genotypes is, however, unexamined. The aim of this study was to investigate the effect of PCL-R and psychopathy on the risk for violent reconvictions among 167 MAOA genotyped alcoholic offenders. Violent reconvictions and PCL-R scores among violent offenders were assessed after a 7-year non-incarcerated follow-up. Regression analysis was used to evaluate the alcohol exposure and age-adjusted effect of PCL-R score and psychopathy on the risk for reconvictions among differing MAOA genotypes. Results suggest that the PCL-R total score predicts impulsive reconvictions among high-activity MAOA offenders (6.8% risk increase for every one-point increase in PCL-R total score, P = 0.015), but not among low-activity MAOA offenders, whereas antisocial behavior and attitudes predicted reconvictions in both genotypes (17% risk increase among high-activity MAOA offenders and 12.8% increase among low-activity MAOA offenders for every one-point increase in factor 2 score). Both narcissistic self-image with related interpersonal style (factor 1 score) and psychopathy (PCL-R ≥ 30) failed to predict future violence. Results suggest that the efficacy of PCL-R is altered by MAOA genotype, alcohol exposure, and age, which seems important to note when PCL-R is used for risk assessments that will have legal or costly preventive work consequences.

Glucocorticoid receptor (NR3C1) gene polymorphisms and onset of alcohol abuse in adolescents.

Onset of alcohol use at an early age increases the risk for later alcohol dependence. We investigated the role of the glucocorticoid receptor (GR) gene (NR3C1) in onset of alcohol use and abuse in 14-year-old adolescents (n=4534). Several NR3C1 polymorphisms were associated with onset of alcohol drinking or drunkenness at this age. Strongest associations were observed in females, with one marker (rs244465) remaining significant after correction for multiple testing (P(adj) =0.0067; odds ratio=1.7, for drunkenness). Our data provide the first evidence that GR modulates initiation of alcohol abuse and reveal a polymorphism that might contribute to susceptibility to addiction.

MAOA alters the effects of heavy drinking and childhood physical abuse on risk for severe impulsive acts of violence among alcoholic violent offenders.

BACKGROUND: A polymorphism in the promoter region of the monoamine oxidase A gene (MAOA) has been shown to alter the effect of persistent drinking and childhood maltreatment on the risk for violent and antisocial behaviors. These findings indicate that MAOA could contribute to inter-individual differences in stress resiliency. METHODS: Recidivism in severe violent crimes was assessed after 8 years of nonincarcerated follow-up in a male sample of 174 impulsive Finnish alcoholic violent offenders, the majority of whom exhibited antisocial (ASPD) or borderline personality disorder (BPD) or both. We examined whether MAOA genotype alters the effects of heavy drinking and childhood physical abuse (CPA) on the risk for committing impulsive recidivistic violent crimes. RESULTS: Logistic regression analyses showed that both heavy drinking and CPA were significant independent predictors of recidivism in violent behavior (OR 5.2, p = 0.004 and OR 5.3, p = 0.003) among offenders having the high MAOA activity genotype (MAOA-H), but these predictors showed no effect among offenders carrying the low MAOA activity genotype (MAOA-L). CONCLUSION: Carriers of the MAOA-H allele have a high risk to commit severe recidivistic impulsive violent crimes after exposure to heavy drinking and CPA.

Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo.

The serotonergic system, including the serotonin 1A (5-HT(1A)) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data show substantial interindividual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT(1A) receptor expression. We used positron emission tomography and [(11)C]WAY-100635 to quantify 5-HT(1A) receptors in a group of 31 healthy and unmedicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. ANOVA of 5-HT(1A) receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p < 0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT(1A) receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p < 0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT(1A) receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.

Effects of MAOA-genotype, alcohol consumption, and aging on violent behavior.

BACKGROUND: Environmental factors appear to interact with a functional polymorphism (MAOA-LPR) in the promoter region of the monoamine oxidase A gene (MAOA) in determining some forms of antisocial behavior. However, how MAOA-LPR modulates the effects of other factors such as alcohol consumption related to antisocial behavior is not completely understood. METHODS: This study examines the conjunct effect of MAOA-LPR, alcohol consumption, and aging on the risk for violent behavior. Recidivism in severe impulsive violent behavior was assessed after 7 to 15 years in a sample of 174 Finnish alcoholic offenders, the majority of whom exhibited antisocial or borderline personality disorder or both, and featured impulsive temperament traits. RESULTS: The risk for committing new acts of violence increased by 2.3% for each kilogram of increase in yearly mean alcohol consumption (p = 0.004) and decreased by 7.3% for every year among offenders carrying the high activity MAOA genotype. In contrast, alcohol consumption and aging failed to affect violent behavior in the low activity MAOA genotyped offenders. MAOA-LPR showed no main effect on the risk for recidivistic violence. CONCLUSIONS: Violent offenders carrying the high activity MAOA genotype differ in several ways from carriers with the low activity MAOA risk allele previously associated with antisocial behavior. Finnish high activity MAOA genotyped risk alcoholics exhibiting antisocial behavior, high alcohol consumption, and abnormal alcohol-related impulsive and uncontrolled violence might represent an etiologically distinct alcohol dependence subtype.

A non-additive interaction of a functional MAO-A VNTR and testosterone predicts antisocial behavior.

A functional VNTR polymorphism in the promoter of the monoamine oxidase A gene (MAOA-LPR) has previously been shown to be an important predictor of antisocial behavior in men. Testosterone analogues are known to interact with the MAOA promoter in vitro to influence gene transcription as well as in vivo to influence CSF levels of the MAO metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in human males. We examined the possible joint effects of testosterone (measured in CSF) and MAOA-LPR genotype on antisocial personality disorder and scores on the Brown-Goodwin Aggression scale in 95 unrelated male criminal alcoholics and 45 controls. The results confirm that MAOA genotype and CSF testosterone interact to predict antisocial behaviors. The MAOA/testosterone interaction also predicted low levels of CSF MHPG, which tentatively suggests the possibility that the interaction may be mediated by a direct effect on gene transcription. If replicated these findings offer plausible explanations for previous inconsistencies in studies of the relationship between testosterone and male human aggression, as well as for how MAOA genotype may influence aggressive behavior in human males.

Genetic approaches to addiction: genes and alcohol.

AIMS: Alcoholism is a chronic relapsing disorder with an enormous societal impact. Understanding the genetic basis of alcoholism is crucial to characterize individuals' risk and to develop efficacious prevention and treatment strategies. METHODS: We examined the available scientific literature to provide an overview of different approaches that are being integrated increasingly to advance our knowledge of the genetic bases of alcoholism. Examples of genes that have been shown to influence vulnerability to alcoholism and related phenotypes are also discussed. RESULTS: Genetic factors account for more than 50% of the variance in alcoholism liability. Susceptibility loci for alcoholism include both alcohol-specific genes acting either at the pharmacokinetic or pharmacodynamic levels, as well as loci moderating neuronal pathways such as reward, behavioral control and stress resiliency, that are involved in several psychiatric diseases. In recent years, major progress in gene identification has occurred using intermediate phenotypes such as task-related brain activation that confer the advantage of increased power and the opportunity of exploring the neuronal mechanisms through which genetic variation is translated into behavior. Fundamental to the detection of gene effects is also the understanding of the interplay between genes as well as genes/environment interactions. Whole Genome Association studies represent a unique opportunity to identify alcohol-related loci in hypothesis-free fashion. Finally, genome-wide analyses of transcripts and chromatin remodeling promise an increase in our understanding of the genome function and of the mechanisms through which gene and environment cause diseases. CONCLUSIONS: Although the genetic bases of alcoholism remain largely unknown, there are reasons to think that more genes will be discovered in the future. Multiple and complementary approaches will be required to piece together the mosaic of causation.

A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response.

The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10-4) and higher plasma cotinine levels (p = 7.0 × 10-5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.

The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations.

Schizophrenia is a complex psychiatric disorder with both genetic and environmental components and is thought to be in part neurodevelopmental in origin. The DISC1 gene has been linked to schizophrenia in two independent Caucasian populations. The DISC1 protein interacts with a variety of proteins including FEZ1, the mammalian homolog of the Caenorhabditis elegans unc-76 protein, which is involved in axonal outgrowth. Variation at the FEZ1 gene has been associated with schizophrenia in a large Japanese cohort. In this study, nine SNP markers at the FEZ1 locus were genotyped in two populations. A North American Caucasian cohort of 212 healthy controls, 178 schizophrenics, 79 bipolar disorder, and 58 with schizoaffective disorder, and an African American cohort of 133 healthy controls, 162 schizophrenics, and 28 with schizoaffective disorder. No association to schizophrenia, bipolar disorder or schizoaffective disorder was found for any of the nine markers typed in these populations at the allelic or the genotypic level. Additionally no association was found in either population between specific haplotypes and any of the psychiatric disorders. Variation at the FEZ1 locus does not play a significant role in the etiology of schizophrenia, bipolar disorder or schizoaffective disorder in North American Caucasian or African American populations.Neuropsychopharmacology (2007) 32, 190-196. doi:10.1038/sj.npp.1301177; published online 16 August 2006.

Increased anxiety and other similarities in temperament of alcoholics with and without antisocial personality disorder across three diverse populations.

According to Cloninger's model, type I alcoholics are thought to be innately vulnerable to anxiety and depression. In contrast, type II alcoholics are thought to have increased likelihood of antisocial personality disorder (ASPD) and reduced anxiety. However, allostatic activations of stress, anxiety, and dysphoria may be a common thread in alcohol use disorders (AUDs). Our aim was to find commonalities and differences in temperament of alcoholics with and without ASPD in three diverse populations. By sib-sib comparisons, we also evaluated the extent to which the temperament traits were moderated by familial factors including inheritance. We compared harm avoidance (HA), novelty seeking (NS), and reward dependence (RD) in alcoholics with ASPD, alcoholics without ASPD, and controls. Correlations for each temperament dimension were evaluated in pairs of siblings concordant and discordant for AUD. Participants were derived from three independent populations: Finnish Caucasians (N=453, men=100%, including a sample of alcoholic criminals), a Plains American Indian community sample (N=378; men=42%), and a subset of the familial and predominantly Caucasian Collaborative Study on the Genetics of Alcoholism (COGA) sample (N=967, men=47%). In all the three populations, both alcoholics with and without ASPD were higher in HA than controls. The increase of HA among alcoholics as compared to controls ranged from 54% to 12%. In two populations (COGA and Finns), NS was highest in alcoholics with ASPD, intermediate in alcoholics without ASPD, and lowest in controls. HA levels were correlated in sib-pairs concordant (either affected or unaffected) for AUD but not in discordant pairs. In conclusions, despite cultural diversity and different modes of ascertainment we found a consistent pattern of elevated HA in all groups of alcoholics, including alcoholics with ASPD. Even in alcoholics with long-term exposure to the anxiogenic effects of repeated cycles of alcohol withdrawal, genetic and other familial influences seem to play a role in moderating anxiety.

The role of anxiety symptoms in school performance in a community sample of children and adolescents.

BACKGROUND: Anxiety symptoms are relatively common among children and adolescents and can interfere with functioning. The prevalence of anxiety and the relationship between anxiety and school performance were examined among elementary, middle, and high school students. METHODS: Samples of elementary (N = 131, age 8-10 years), middle (N = 267, age 11-13 years), and high school (N = 80, age 14-16 years) children were recruited from four public schools in a predominantly middle-class community in Catania, Italy. Children completed the Multidimensional Anxiety Scale for Children (MASC). T-scores were computed for the MASC total scores, and considered to be in the anxious range if 65 or above. Current academic grades were obtained from school records. RESULTS: Of the 478 children, 35 (7.3%) had a MASC T-score in the anxious range. The rate of children in the anxious range was 2.3% in elementary, 7.9% in middle, and 15.9% in high school (chi2 = 7.8, df = 2, p < 0.05), and was 14.1% among students with insufficient grades, 9.4% among those with sufficient grades, and 3.9% among those with good or very good grades (chi2 = 11.68, df = 2, p < 0.01). CONCLUSION: In this community sample of children and adolescents attending elementary through high school, the prevalence of abnormally high self-reported levels of anxiety increased in frequency with age and was negatively associated with school performance.

Deconstruction of vulnerability to complex diseases: enhanced effect sizes and power of intermediate phenotypes.

The deconstruction of vulnerability to complex disease with the help of intermediate phenotypes, including the heritable and disease-associated endophenotypes, is a legacy of Henri Begleiter. Systematic searches for genes influencing complex disorders, including bipolar disorder, have recently been completed using whole genome association (WGA), identifying a series of validated loci. Using this information, it is possible to compare effect sizes of disease loci discovered in very large samples to the effect sizes of replicated functional loci determining intermediate phenotypes that are of essential interest in psychiatric disorders. It is shown that the genes influencing intermediate phenotypes tend to have a larger effect size. Furthermore, the WGA results reveal that the number of loci of large effect size for complex diseases is limited, and yet multiple functional loci have already been identified for intermediate phenotypes relevant to psychiatric diseases, and without the benefit of WGA.

Newer antipsychotics and the rabbit syndrome.

BACKGROUND: Rabbit syndrome is a movement disorder that is associated with long-term exposure to neuroleptic medications. Of particular interest and importance is the risk of rabbit syndrome with exposure to the newer atypical antipsychotics. Our recent experience with such a case brought to light the importance of exploring this risk. METHODS: MEDLINE and PubMed (1972-2006) databases were searched for English language articles using the keywords rabbit syndrome, tardive dyskinesia, antipsychotic, extrapyramidal symptoms and side effects. A recent case study is used to expand upon the literature available on newer antipsychotics and rabbit syndrome. RESULTS: We reviewed papers that addressed the following aspects of rabbit syndrome 1) the clinical manifestations 2) prevalence and risk factors, 3) etiopathogenesis 4) older antipsychotics and rabbit syndrome 5) newer antipsychotics, 6) treatment options. Moreover, we report a case of RS in a 50 year old white female, diagnosed with bipolar I disorder, that, after the discontinuation of risperidone, developed involuntary movements of the mouth that were fine, rhythmic and rapid, along the vertical axis, and without involvement of the tongue. After the re-introduction of risperidone, the symptoms decreased in a few hours and disappeared after 3 days. CONCLUSION: Eleven cases of rabbit syndrome have been documented since the implementation of newer antipsychotics. Future research is needed to better understand the etiopathogenesis of rabbit syndrome in psychiatric populations treated with the atypical antipsychotics. Understanding the differences and similarities of rabbit syndrome and tardive dyskinesia is crucial to the creation of a successful treatment paradigm.

Genome-Wide Association of Heroin Dependence in Han Chinese.

Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls. Analysis using the diagnostic criteria of heroin dependence yielded suggestive evidence for association between variants in the genes CCDC42 (coiled coil domain 42; p = 2.8x10-7) and BRSK2 (BR serine/threonine 2; p = 4.110-6). In addition, we found evidence for risk variants within the ARHGEF10 (Rho guanine nucleotide exchange factor 10) gene on chromosome 8 and variants in a region on chromosome 20q13, which is gene-poor but has a concentration of mRNAs and predicted miRNAs. Gene-based association analysis identified genome-wide significant association between variants in CCDC42 and heroin addiction. Additionally, when we investigated shared risk variants between heroin addiction and risk of other addiction-related and psychiatric phenotypes using polygenic risk scores, we found a suggestive relationship with variants predicting tobacco addiction, and a significant relationship with variants predicting schizophrenia. Our genome wide association study of heroin dependence provides data in a novel sample, with functionally plausible results and evidence of genetic data of value to the field.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.

OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

The genetic basis of addictive disorders.

Addictions are common, chronic, and relapsing diseases that develop through a multistep process. The impact of addictions on morbidity and mortality is high worldwide. Twin studies have shown that the heritability of addictions ranges from 0.39 (hallucinogens) to 0.72 (cocaine). Twin studies indicate that genes influence each stage from initiation to addiction, although the genetic determinants may differ. Addictions are by definition the result of gene × environment interaction. These disorders, which are in part volitional, in part inborn, and in part determined by environmental experience, pose the full range of medical, genetic, policy, and moral challenges. Gene discovery is being facilitated by a variety of powerful approaches, but is in its infancy. It is not surprising that the genes discovered so far act in a variety of ways: via altered metabolism of drug (the alcohol and nicotine metabolic gene variants), via altered function of a drug receptor (the nicotinic receptor, which may alter affinity for nicotine but as discussed may also alter circuitry of reward), and via general mechanisms of addiction (genes such as monoamine oxidase A and the serotonin transporter that modulate stress response, emotion, and behavioral control). Addiction medicine today benefits from genetic studies that buttress the case for a neurobiologic origin of addictive behavior, and some general information on familially transmitted propensity that can be used to guide prevention. A few well-validated, specific predictors such as OPRM1, ADH1B, ALDH2, CHRNA5, and CYP26 have been identified and can provide some specific guidance, for example, to understand alcohol-related flushing and upper GI cancer risk (ADH1B and AKLDH2), variation in nicotine metabolism (CYP26), and, potentially, naltrexone treatment response (OPRM1). However, the genetic predictors available are few in number and account for only a small portion of the genetic variance in liability, and have not been integrated into clinical nosology or care.

Associations between variation in CHRNA5-CHRNA3-CHRNB4, body mass index and blood pressure in the Northern Finland Birth Cohort 1966.

BACKGROUND: The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation. METHODOLOGY/PRINCIPAL FINDINGS: We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5-CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by -1.21 (95% CI -2.01, -0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of -0.38 (-0.68, -0.08) kg/m(2) per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing. CONCLUSIONS: Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible interactions, and to understand the mechanisms behind.