Matti Virkkunen

Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior

Relationships of impulsive and nonimpulsive violent behavior to cerebrospinal fluid (CSF) monoamines and their metabolic concentrations were studied in thirty-six violent offenders. A relatively low 5-hydroxyindoleacetic acid (5HIAA) concentration was found in the CSF of impulsive violent offenders. This was not true for the offenders who had premeditated their acts. Other CSF monoamine or metabolite concentrations were not significantly different between the two groups. Of the groups studied, impulsive violent offenders who had attempted suicide had the lowest 5HIAA levels. A low CSF 5HIAA concentration may be a marker of impulsivity rather than violence.

Breakfast skipping and health-compromising behaviors in adolescents and adults

Objective: To investigate which sociodemographic factors and behaviors are associated with breakfast skipping in adolescents and adults.Design: Five birth cohorts of adolescent twins and their parents received an extensive behavioral and medical self-report questionnaire that also assessed breakfast-eating frequency.Setting: Finland, 1991–1995.Subjects: A population sample of 16-y-old girls and boys (n=5448) and their parents (n=4660).Results: Parental breakfast eating was the statistically most significant factor associated with adolescent breakfast eating. Smoking, infrequent exercise, a low education level at 16, female sex, frequent alcohol use, behavioral disinhibition, and high body mass index (BMI) were significantly associated with adolescent breakfast skipping. In adults, smoking, infrequent exercise, low education level, male sex, higher BMI, and more frequent alcohol use were associated with breakfast skipping. In the adult sample, older individuals had breakfast more often than younger ones. Both adults and adolescents who frequently skipped breakfast were much more likely to exercise very little compared to those who skipped breakfast infrequently. Breakfast skipping was associated with low family socioeconomic status in adults and adolescent boys, but not in girls. Breakfast skipping clustered moderately with smoking, alcohol use, and sedentary lifestyle in both adults and adolescents.Conclusions: Breakfast skipping is associated with health-compromising behaviors in adults and adolescents. Individuals and families who skip breakfast may benefit from preventive efforts that also address risk behaviors other than eating patterns.Sponsorship: National Institute of Alcohol Abuse and Alcoholism (AA08315), Academy of Finland (44069), European Union Fifth Framework Program (QLRT-1999-00916), Yrjö Jahnsson Foundation, and Jalmari and Rauha Ahokas Foundation.

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.

Mu opioid receptor gene variants: lack of association with alcohol dependence.

The μ opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse.1,2 This hypothesis is supported by the effects of alcohol on beta-endorphin release,3 of μopioid receptor agonists and antagonists on alcohol consumption,4,5 and by the activation of the dopaminergic reward system by both alcohol and opiates.6 In addition, the murine μopioid receptor locus, Oprm, is implicated as the major quantitative trait locus (QTL) affecting the different levels of morphine consumption between two inbred mouse strains that also exhibit differences in alcohol and cocaine consumption.7,8 Detection of genetic variation affecting OPRM1 expression or μopioid receptor function would be an important step towards understanding the origins of inter-individual variation in response to μ opioid receptor ligands and in diseases of substance dependence.9–12 We directly sequenced the human μopioid receptor locus, OPRM1,13–15 to detect natural variation that might affect function and/or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three non-synonymous substitutions (Ala6Val [rare], Asn40Asp, [0.10–0.16], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C [0.55–0.63]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (US Caucasian [USC, n = 100], Finnish Caucasian [FC, n = 324] and Southwestern American Indian [SAI, n = 367]), were used to perform association and sib-pair linkage analyses with alcohol and drug dependence diagnoses. No significant association of OPRM1 genetic variation to phenotype was observed. This analysis has 80% power to detect a small to moderate effect of OPRM1 variation on alcohol dependence and 100% power to detect effects of the magnitude of the ALDH2*2 variant. While these data do not support a role of the μ opioid receptor in susceptibility to alcohol dependence, the potential relationship between OPRM1 genetic variation and response to endogenous opioids and exogenous opiates can now be investigated.

Urinary free cortisol secretion in habitually violent offenders.

ABSTRACT– Male violent offenders (n= 90) and residivious arsonists (n= 10) were investigated by urinary (24 h) free cortisol measurements at mental examination on a psychiatric department. The measurements were made with competitive protein‐binding radioassay. Only among the habitually violent offenders with antisocial personality were the values low when compared with other violent offenders, antisocial personality without the habitually violent tendency, and male clinic personnel. Poor motivation already in school, truancy, attention deficit and undersocialized aggressive conduct disorder problems seemed to be connected with the low cortisol levels.

Dual origins of Finns revealed by Y chromosome haplotype variation

The Finnish population has often been viewed as an isolate founded 2, 000 years ago via a route across the Gulf of Finland. The founding event has been characterized as involving a limited number of homogeneous founders, isolation, and subsequent rapid population growth. Despite the purported isolation of the population, levels of gene diversity for the Finns at autosomal and mitochondrial DNA loci are indistinguishable from those of other Europeans. Thus, mixed or dual origins for the Finns have been proposed. Here we present genetic evidence for the dual origins of Finns by evaluating the pattern of Y chromosome variation in 280 unrelated males from nine Finnish provinces. Phylogenetic analysis of 77 haplotype configurations revealed two major star-shaped clusters of Y haplotypes, indicative of a population expansion from two common Y haplotypes. Dramatic and quite significant differences in Y haplotype variation were observed between eastern and western regions of Finland, revealing contributions from different paternal types. The geographic distribution and time of expansion for the two common Y haplotypes correlate well with archeological evidence for two culturally and geographically distinct groups of settlers. Also, a northeastern to southwestern gradient of Y haplotype frequencies provides convincing evidence for recent male migration from rural areas into urban Finland.

Serotonin in early onset, male alcoholics with violent behaviour.

Several lines of evidence suggest that abnormal brain serotonin metabolism may occur in early onset, type 2 alcoholism in men. Low cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration has been found to be associated with a history of paternal alcoholism, and abnormal oral glucose tolerance tests (tendency to low blood glucose nadir) in subjects who are prone to exhibit impulsive, aggressive behaviour under the influence of alcohol. Moreover, a low ratio of the concentrations of tryptophan and other large neutral amino acids in plasma seems to correlate with early onset alcohol abuse and violent tendencies. More knowledge is required about neurochemical changes in homogenous subgroups of alcoholics such as the putative type 2 so as to understand which of the relationships are causative and to provide treatment strategies for alcoholism and its complications.

Serum cholesterol levels in homicidal offenders. A low cholesterol level is connected with a habitually violent tendency under the influence of alcohol

Serum cholesterol fasting concentrations were measured in 280 male homicidal offenders. Those with an antisocial personality or an intermittent explosive disorder with a habitually violent tendency in both when under the influence of alcohol showed a lower mean level of serum cholesterol than did other offenders. The results were also compatible with the hypotheses that antisocial personality consists of two groups. The exact reason for the finding is not clear but it could be connected with an enhanced insulin secretion.

Serum Cholesterol in Antisocial Personality

Serum cholesterol fasting concentrations were measured in 274 subjects with personality disorders, who had committed offences. Of these subjects, 139 were found to possess the antisocial personality (sociopathy or psychopathy). With standardized ages, the group of subjects with antisocial personality had a clearly lower mean level of serum cholesterol than the group with other personality disorders which was used as a control group. The use of a mean male population with standardized ages as a control group further emphasized the low values of the serum cholesterol of the antisocial personality group.

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.