Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype.

Artificially selected model organisms can reveal hidden features of the genetic architecture of the complex disorders that they model. Addictions are disease phenotypes caused by different intermediate phenotypes and pathways and thereby are potentially highly polygenic. High responder (bHR) and low responder (bLR) rat lines have been selectively bred (b) for exploratory locomotion (EL), a behavioral phenotype correlated with novelty-seeking, impulsive response to reward, and vulnerability to addiction, and is inversely correlated with spontaneous anxiety and depression-like behaviors. The rapid response to selection indicates loci of large effect for EL. Using exome sequencing of HR and LR rats, we identified alleles in gene-coding regions that segregate between the two lines. Quantitative trait locus (QTL) analysis in F2 rats derived from a bHR × bLR intercross confirmed that these regions harbored genes affecting EL. The combined effects of the seven genome-wide significant QTLs accounted for approximately one-third of the total variance in EL, and two-thirds of the variance attributable to genetic factors, consistent with an oligogenic architecture of EL estimated both from the phenotypic distribution of F2 animals and rapid response to selection. Genetic association in humans linked APBA2, the ortholog of the gene at the center of the strongest QTL, with substance use disorders and related behavioral phenotypes. Our finding is also convergent with molecular and animal behavioral studies implicating Apba2 in locomotion. These results provide multilevel evidence for genes/loci influencing EL. They shed light on the genetic architecture of oligogenicity in animals artificially selected for a phenotype modeling a more complex disorder in humans.

Fire-setting performed in adolescence or early adulthood predicts schizophrenia: a register-based follow-up study of pre-trial offenders.

BACKGROUND: Aggressive and disruptive behaviours often precede the onset of serious mental illnesses. Fire-setting is a type of crime that is associated with psychotic disorders. AIM: The aim of this prospective follow-up study was to investigate if fire-setting performed in adolescence or early adulthood was associated with future diagnoses of schizophrenia or schizoaffective disorder. METHODS: The consecutive sample consisted of 111 Finnish 15-25-year old males with fire-setting crimes, decreed to a pre-trial forensic psychiatric examination in 1973-1998, and showing no past nor current psychosis at the time of examination. For each firesetter, four age-, gender-, and place of birth-matched controls were randomly selected from the Central Population Register. The subjects were followed until the death of the individual, until they moved abroad, or until the end of 2012. RESULTS: Fourteen firesetters (12.6%) and five controls (1.1%) were diagnosed with either schizophrenia or schizoaffective disorder later in life, corresponding to a hazard ratio of 12.5. The delay between the fire-setting offense and the future diagnosis was on average nearly 10 years. CONCLUSIONS: Young male offenders undergoing a forensic psychiatric examination because of fire-setting crimes had a significant propensity for schizophrenia and schizoaffective disorder. Accurate assessments should be made both during imprisonment and later in life to detect possible psychotic signs in these individuals.

A population-specific HTR2B stop codon predisposes to severe impulsivity.

Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency > 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.

Hospital-treated suicide attempts among Finnish fire setters: a follow-up study.

BACKGROUND: High rates of attempted and completed suicide have been reported among offenders, but there has been little attention in this respect to fire setters specifically. Aim Our aim was to investigate hospital-treated suicide attempts among male fire setters. METHODS: For each of a consecutive series of 441 pre-trial fire setters, four controls matched for age, gender and place of birth were randomly selected from the Central Population Register. Data on hospitalisation and causes of death over a 39-year period were obtained from the Finnish national registers. RESULTS: The prevalence of suicide attempts was significantly higher among fire setters than among controls. Approximately every fifth fire setter had made at least one suicide attempt which had required hospital treatment. The most common method chosen was intentional self-poisoning or exposure to noxious substances. More than 1 in 10 fire setters with at least one hospitalisation for suicide-related behaviour eventually completed suicide. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: More attention should be paid to detecting and managing suicidal behaviours among fire setters as they are a high-risk group and accurate identification of their needs in this respect may not only be life-saving but also reduce recidivism. Copyright © 2015 John Wiley & Sons, Ltd.

Psychopathic traits among a consecutive sample of Finnish pretrial fire-setting offenders.

BACKGROUND: Psychopathy, a severe disorder of personality, is well represented in the criminal and forensic psychiatric population and is significantly associated with increased risk of violence and crime. Fire-setting is a major source of property damage, injury, and death in many Western countries. The primary aim of this study was to evaluate psychopathic traits in a consecutive sample of Finnish male pretrial fire-setting offenders. Further, we wanted to investigate whether fire-setting recidivists show higher traits of psychopathy than one-time firesetters and whether exclusive firesetters show lower traits of psychopathy than those with criminal versatility. METHODS: The forensic psychiatric examination statements for male firesetters who underwent a pretrial forensic psychiatric evaluation during a 10-year period (1989 -1998) were reviewed. The sample comprised 129 firesetters with normal IQ, 41 of whom were fire-setting recidivists. Fifty men were exclusive firesetters. Assessment of psychopathy-like personality character was performed using the 20-item Hare Psychopathy Checklist-Revised. RESULTS: Two individuals (1.6%, 95% Cl: 0.0-3.7) scored ≥30 points and 19 (14.7%, 95% Cl: 8.6-20.8) ≥ 25 points on the PCL-R. The mean PCL-R total score was 16.1 (SD 6.88), the mean Factor 1 score 5.0 (SD 3.41), and the mean Factor 2 score 9.9 (SD 3.86). No significant differences emerged between the recidivists and the one-time firesetters. The versatile firesetters exhibited significantly higher mean total and factor scores than the exclusive ones. CONCLUSION: Among firesetters, there is a subgroup of persons with significant psychopathic traits, which should be recognized in legal and health care organizations. Although psychopathy was associated with greater criminal versatility, it bore no relationship to fire-setting recidivism.

Genetic variation in human NPY expression affects stress response and emotion.

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations.

BACKGROUND: Ethanol is metabolized by 2 rate-limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde that is subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non-East Asian populations by performing systematic haplotype association analyses to maximize the chances of capturing functional variation. METHODS: Haplotype-tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case control sample sizes were the following: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; and Southwestern American (SW) Indians: 317, 72. RESULTS: In all four populations, as well as HapMap populations, 5 haplotype blocks were identified across the ADH gene cluster: (i) ADH5-ADH4; (ii) ADH6-ADH1A-ADH1B; (iii) ADH1C; (iv) intergenic; (v) ADH7. The ALDH1A1 gene was defined by 4 blocks and ALDH2 by 1 block. No haplotype or SNP association results were significant after correction for multiple comparisons; however, several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3' UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317, respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians. CONCLUSIONS: The systematic evaluation of alcohol-metabolizing genes in four non-East Asian populations has shown only modest associations with AD, largely for ALDH1A1 and ADH4. A concentration of signals for AD with ALDH1A1 yin yang haplotypes in several populations warrants further study.

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.

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.

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.

Recidivistic offending and mortality in alcoholic violent offenders: a prospective follow-up study.

Predictive data supporting prevention of violent criminality are scarce. We examined risk factors for recidivism and mortality among non-psychotic alcoholic violent offenders, the majority having antisocial or borderline personality disorders, or both, which is a group that commits the majority of violent offences in Finland. Criminal records and mortality data on 242 male alcoholic violent offenders were analysed after a 7- to 15-year follow-up, and compared between themselves and with those of 1210 age-, sex- and municipality-matched controls. Recidivism and mortality rates were high. The risk of recidivistic violence was increased by antisocial or borderline personality disorder, or both, childhood maltreatment, and a combination of these. A combination of borderline personality disorder and childhood maltreatment was particularly noxious, suggesting an additive risk increase for a poor outcome. Accurate diagnosis and careful childhood interview may help to predict recidivism and premature death.

Low non-oxidative glucose metabolism and violent offending: an 8-year prospective follow-up study.

Violent offenders have abnormalities in their glucose metabolism as indicated by decreased glucose uptake in their prefrontal cortex and a low blood glucose nadir in the glucose tolerance test. We tested the hypothesis that low non-oxidative glucose metabolism (NOG) predicts forthcoming violent offending among antisocial males. Glucose metabolism was measured using the insulin clamp method among 49 impulsive, violent, antisocial offenders during a forensic psychiatric examination. Those offenders who committed at least one new violent crime during the 8-year follow-up had a mean NOG of 1.4 standard deviations lower than non-recidivistic offenders. In logistic regression analysis, NOG alone explained 27% of the variation in the recidivistic offending. Low non-oxidative metabolism may be a crucial component in the pathophysiology of habitually violent behavior among subjects with antisocial personality disorder. This might suggest that substances increasing glycogen formation and decreasing the risk of hypoglycemia might be potential treatments for impulsive violent behavior.

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.

Sleep in conduct-disordered adolescents--a polysomnographic and spectral power analysis study.

The aim of the present study was to characterize sleep in conduct-disordered adolescents using polysomnography and spectral power analysis. The two hypotheses were that conduct disorder would be associated with objective sleep problems, and that conduct disorder--as a precursor of adult antisocial personality disorder--would be associated with the same kind of abnormal sleep architecture, with both increased deep sleep and delta power, as previously reported in antisocial personality disorder. The patients consisted of 15 adolescents (age range 13-17 years, mean age 14.7 years) with histories of antisocial behavior so functionally impairing that they were ordered by child welfare to undergo a psychosocial evaluation in a closed social services ward. The healthy age-matched controls comprised 20 volunteers recruited with a newspaper advertisement. Opposite to earlier subjective sleep studies among conduct-disordered children, no significant differences in sleep parameters were observed between the two groups. The adolescents with conduct disorder slept a little bit longer, but the percentage amount of different sleep stages did not differ significantly between the two groups. Relative spectral power of sleep, delta power in particular, was similar in both groups, assessed in total sleep time as well as in first half of it. Different alternative explanations for these findings are discussed.

Firesetting and general criminal recidivism among a consecutive sample of Finnish pretrial male firesetters: A register-based follow-up study.

The rate of criminal reoffending among firesetters varies greatly. Our aim was to investigate firesetting and general criminal recidivism in a consecutive sample of Finnish males who were sent for a forensic psychiatric examination (FPE)1 after committing firesetting offenses. We also wanted to evaluate the relationships between psychopathy and criminal recidivism, and between schizophrenia-spectrum disorders and criminal recidivism. The sample comprised 113 firesetters with a mean age of 32.8 years, and the average follow-up time was 16.9 years. The FPE statements of the firesetters were reviewed and psychiatric diagnoses were collected. The psychopathy assessments were based on the 20-item Hare Psychopathy Checklist-Revised (PCL-R). Information on reoffending was gathered from the Finnish National Police Register. During the follow-up 20 (18%) persons were registered for a new firesetting and 84 (74%) for any new offense. Firesetters with high traits (PCL-R ≥ 25) of psychopathy were more likely than those with low traits (PCL-R < 25) to reoffend with any crime during the follow-up. The risk of general criminal recidivism was lower among firesetters with a schizophrenia-spectrum disorder than among those with non-psychotic disorders. Conclusively, both firesetting and general criminal-recidivism rates were high in this sample of offenders.

Energy substrate metabolism among habitually violent alcoholic offenders having antisocial personality disorder.

A large proportion of violent offences in Western countries are attributable to antisocial personality disorder (APD). Several studies have shown abnormal lipid, carbohydrate and low cerebrospinal fluid (CSF) monoamine metabolite levels in habitually violent alcoholic offenders with APD, but it is not clear how these biochemical abnormalities are related to each other in this disorder. We aimed to study energy substrate metabolism among habitually violent offenders with APD. Insulin sensitivity (euglycemic insulin clamp), basal energy expenditure (indirect calorimetry), and CSF 5-hydroxyindoleacetic acid (5-HIAA) measurements were performed on 96 habitually violent antisocial male alcoholic offenders and on 40 normal male controls. Habitually violent, incarcerated offenders with APD had significantly lower non-oxidative glucose metabolism, basal glucagon, and free fatty acids when compared with normal controls, but glucose oxidation and CSF 5-HIAA did not differ markedly between these groups. The effect sizes for lower non-oxidative glucose metabolism among incarcerated and non-incarcerated APD subjects were 0.73 and 0.51, respectively, when compared with controls, indicating that this finding was not explained by incarceration. Habitually violent offenders with APD have markedly lower glucagon and non-oxidative glucose metabolism when compared with healthy controls, and these findings were more strongly associated with habitual violent offending than low CSF 5-HIAA levels, a well-established marker for impulsive violent behavior. Follow-up studies are needed to confirm if abnormal glucose and lipid metabolism can be used to predict violent offending over the course of the APD offender's life span.

Tridimensional Personality Questionnaire data on alcoholic violent offenders: specific connections to severe impulsive cluster B personality disorders and violent criminality.

BACKGROUND: The validity of traditional categorical personality disorder diagnoses is currently re-evaluated from a continuous perspective, and the evolving DSM-V classification may describe personality disorders dimensionally. The utility of dimensional personality assessment, however, is unclear in violent offenders with severe personality pathology. METHODS: The temperament structure of 114 alcoholic violent offenders with antisocial personality disorder (ASPD) was compared to 84 offenders without ASPD, and 170 healthy controls. Inclusion occurred during a court-ordered mental examination preceded by homicide, assault, battery, rape or arson. Participants underwent assessment of temperament with the Tridimensional Personality Questionnaire (TPQ) and were diagnosed with DSM-III-R criteria. RESULTS: The typical temperament profile in violent offender having ASPD comprised high novelty seeking, high harm avoidance, and low reward dependence. A 21% minority scored low in trait harm avoidance. Results, including the polarized harm avoidance dimension, are in accordance with Cloninger's hypothesis of dimensional description of ASPD. The low harm avoidance offenders committed less impulsive violence than high harm avoidance offenders. High harm avoidance was associated with comorbid antisocial personality disorder and borderline personality disorder. CONCLUSION: Results indicate that the DSM based ASPD diagnosis in alcoholic violent offenders associates with impulsiveness and high novelty seeking but comprises two different types of ASPD associated with distinct second-order traits that possibly explain differences in type of violent criminality. Low harm avoidance offenders have many traits in common with high scorers on the Hare Psychopathy Checklist-Revised (PCL-R). Results link high harm avoidance with broad personality pathology and argue for the usefulness of self-report questionnaires in clinical praxis.

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.

Haplotype-based localization of an alcohol dependence gene to the 5q34 {gamma}-aminobutyric acid type A gene cluster.

CONTEXT: Pharmacobehavioral and pharmacogenetic evidence links gamma-aminobutyric acid type A (GABA(A)) receptors and chromosomal regions containing GABA(A) receptor genes to ethanol-related responses. The GABA(A) gene cluster on chromosome 5q34 is of particular interest in the genetics of alcohol dependence because of the gamma2 subunit requirement for ethanol's modulatory action on GABA(A) receptors, previous linkage findings in mice and humans implicating both GABRA6 and GABRG2, and reported associations of GABRA6, GABRB2, and GABRG2 alleles with alcohol dependence. OBJECTIVE: To determine whether variation at the 5q34 GABA(A) gene cluster is implicated in differential susceptibility to alcohol dependence. METHODS: Two large psychiatrically interviewed samples, a Southwestern Native American population sample (N = 433) and a Finnish sample (N = 511) with alcohol-dependent subjects and unaffected individuals, were genotyped for 6 single nucleotide polymorphisms at the 5q34 GABA(A) gene cluster. In addition to sib-pair linkage and case-control association analyses, linkage disequilibrium mapping with haplotypes was used. RESULTS: Sib-pair linkage of GABRG2 to alcohol dependence was observed in Finns (P = .008). Association of the GABRB2 1412T allele with alcohol dependence was detected in both populations (Finns, P = .01; Southwestern Native Americans, P = .008), and the GABRA6 1519T allele was associated in both Finns (P = .01) and Southwestern Native Americans (P = .03). Linkage disequilibrium mapping with 3-locus haplotypes yielded evidence for an alcohol-dependence locus at the GABA(A) gene cluster region in both populations. The most highly significant signals were at 3-locus haplotypes that included 1 or more GABRA6 polymorphisms, with the peak signal at a GABRA6 3-locus haplotype (Finns, empirical P = .004; Southwestern Native Americans, empirical P = .02). CONCLUSIONS: We detected sib-pair linkage of 5q34 GABA(A) receptor genes to alcohol dependence in Finns and found association both in Finns and in Southwestern Native Americans. In both populations, the haplotype localization implicates the region containing the Pro385Ser GABRA6 polymorphism and 2 other polymorphisms at GABRA6.

Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations.

CONTEXT: Tryptophan hydroxylase 2 (TPH2) encodes the rate-limiting enzyme for brain serotonin biosynthesis. It was recently reported that the TPH2 haplotype was linked to depression in humans. OBJECTIVE: To determine the association of TPH2 with suicide attempt, major depression, and a neurochemical intermediate phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid. DESIGN: We resequenced TPH2 coding, 5' promoter, 3'-untranslated region, and splice junction regions in 190 individuals selected for ethnic and clinical diversity, determined haplotype structure using 15 single nucleotide polymorphisms spanning 106 kilobases (kb), and performed linkage analysis in 1798 cases and controls representing 4 populations (657 African Americans, including 104 suicide attempters and 135 with major depression; 513 Finnish whites, including 150 suicide attempters; 146 US whites, including 81 with depression, anxiety disorder, or both; and 482 southwestern American Indians, including 123 suicide attempters and 191 with depression, anxiety disorder, or both) and in 94 Finnish whites for cerebrospinal fluid 5-hydroxyindoleacetic acid levels. RESULTS: Sixteen single nucleotide polymorphisms, including Pro206Ser, were detected. The 15-locus panel defined and maximized information content from 2 haplotype blocks in whites, 3 haplotype blocks in African Americans, and the single haplotype block spanning TPH2 in southwestern American Indians. Among common Block1b haplotypes were 2 in yin and yang (opposite) configuration, indicating ancient origin. The yin haplotype, 212121, was increased in frequency in suicide attempters in both populations tested (Finnish whites and African Americans). It was associated with major depression and anxiety disorders in US whites and with major depression in African Americans. The yin haplotype was moderately predictive of lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in controls but not in cases. CONCLUSION: Haplotype linkage of TPH2 to suicide attempt and major depression and to a mediating phenotype, cerebrospinal fluid 5-hydroxyindoleacetic acid, provides preliminary evidence of a functional locus potentially within a haplotype block at least 52 kb in size.