Niklas Nordquist

Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene

Previous research has demonstrated that a polymorphism in the serotonin transporter gene (5-HTTLPR) and adverse psychosocial circumstances interact to predict depression. The purpose of the present study was to explore the extent to which sex modulates these effects. Eighty-one boys and 119 girls (16-19 years old) were interviewed about psychosocial background variables and genotyped for the 5-HTT promoter polymorphism. There were two main results. First, boys and girls carrying the short 5-HTTLPR allele react to different kinds of environmental factors. Whereas males were affected by living in public housing rather than in own owned homes and by living with separated parents, females were affected by traumatic conflicts within the family. Second, the responses of males and females carrying the short 5-HTTLPR allele to environmental stress factors go in opposite directions. Thus, whereas females tend to develop depressive symptoms, males seem to be protected from depression. The results suggest that both the molecular and the psychosocial mechanisms underlying depression may differ between boys and girls.

Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats

Rheumatoid arthritis (RA) is a chronic and genetically complex inflammatory disorder that leads to erosive destruction of peripheral joints. The use of animal models mimicking RA, such as pristane-induced arthritis (PIA) in rats, should facilitate its genetic analysis. Pristane is a non-immunogenic synthetic oil that, after a single subcutaneous injection into DA rats, induces arthritis restricted to peripheral joints with a chronic relapsing disease course. To identify genes involved in the control of chronic arthritis, we made crosses between susceptible DA rats and resistant E3 rats and analysed the progeny with microsatellite markers covering the entire rat genome. Our results show that different arthritis phenotypes are associated with different chromosomal loci. Loci on chromosomes 4 and 6 (Pia2 and Pia3) influence arthritis onset, whereas a locus on chromosome 12 (Pia4) is associated with severity and joint erosion. We found that chronicity is associated with a different set of loci, one on chromosome 4 and the other on chromosome 14 (Pia5, Pia6). These findings demonstrate for the first time that different phases of a chronic self-perpetuative disease which mimics RA are associated with distinct sets of genes.

Serotonin, genetic variability, behaviour, and psychiatric disorders : a review

Abstract Brain monoamines, and serotonin in particular, have repeatedly been shown to be linked to different psychiatric conditions such as depression, anxiety, antisocial behaviour, and dependence. Many studies have implicated genetic variability in the genes encoding monoamine oxidase A (MAOA) and the serotonin transporter (5HTT) in modulating susceptibility to these conditions. Paradoxically, the risk variants of these genes have been shown, in vitro, to increase levels of serotonin, although many of the conditions are associated with decreased levels of serotonin. Furthermore, in adult humans, and monkeys with orthologous genetic polymorphisms, there is no observable correlation between these functional genetic variants and the amount or activity of the corresponding proteins in the brain. These seemingly contradictory data might be explained if the association between serotonin and these behavioural and psychiatric conditions were mainly a consequence of events taking place during foetal and neonatal brain development. In this review we explore, based on recent research, the hypothesis that the dual role of serotonin as a neurotransmitter and a neurotrophic factor has a significant impact on behaviour and risk for neuropsychiatric disorders through altered development of limbic neurocircuitry involved in emotional processing, and development of the serotonergic neurons, during early brain development.

Platelet MAO activity and the 5-HTT gene promoter polymorphism are associated with impulsivity and cognitive style in visual information processing.

RationaleLow capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning.ObjectivesThe effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for.ResultsLow platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities.ConclusionsThe two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.

Genetic linkage analysis of collagen-induced arthritis in the mouse.

The genetic susceptibility to collagen‐induced arthritis (CIA) in mice, the most commonly used model for rheumatoid arthritis, has been analyzed. The highly susceptible B10.RIII strain was crossed with the resistant RIIIS/J strain and the F2 intercross mice were subjected to genomic screening using microsatellite markers. These strains share the MHC region on chromosome 17, known to be of importance in CIA (this locus is named Mcia1). The same cross has earlier been used to map the major genes outside the MHC controlling chronic relapsing experimental allergic encephalomyelitis (EAE). It was found that the major locus controlling CIA (Mcia2; lod 4.12) was located on chromosome 3 in the same region as one of the major loci controlling EAE (Eae3). The linkage was reproduced in a mouse strain in which the locus was isolated on the B10.RIII background at the N4I2 generation. A second putative locus was identified on chromosome 13 (lod 3.13). The present finding identifies new loci outside the MHC controlling CIA and provides evidence that mouse CIA is controlled by polymorphic genes.

MAOA genotype, family relations and sexual abuse in relation to adolescent alcohol consumption.

The aim of the present study was to investigate MAOA gene–environment (G*E) interactions in relation to adolescent alcohol consumption. In the county of Västmanland, Sweden, all 17–18‐year‐old students were asked to complete an anonymous questionnaire and provide a saliva sample during class hours. A total of 2263 students completed the questionnaire (77.4%) and a saliva sample was provided by 2131 participants. Failed MAOA u‐variable number of tandem repeats (VNTR) genotype analyses and internal non‐responses left 851 boys and 735 girls (total n = 1586) to be investigated. Alcohol use disorder identification test was used to measure hazardous alcohol consumption. MAOA u‐VNTR was used to measure biological risk in interaction with poor family relations and experience of sexual abuse. The model was also adjusted for non‐independent socioeconomic variables, separated parents, type of housing and parental unemployment. Results showed that the MAOA u‐VNTR, in interaction with psychosocial risk factors, such as the quality of family relations and sexual abuse, was related to high alcohol consumption among adolescents. Girls, carrying the long MAOA u‐VNTR variant showed a higher risk of being high alcohol consumers, whereas among boys, the short allele was related to higher alcohol consumption. The present study supports the hypothesis that there is a relation between MAOA u‐VNTR and alcohol consumption and that this relation is modulated by environmental factors. Furthermore, the present study also supports the hypothesis that there is a sex difference in the G*E interaction.

The effect of 5-HTT gene promoter polymorphism on impulsivity depends on family relations in girls

The short (S) allele of the 5-HTT gene promoter region polymorphism (5-HTTLPR), in combination with adverse environmental influence, leads to higher likelihood of depression. Impulsivity has been related to low serotonin turnover, poor regulation of affect, and problems in the family, including child maltreatment. The current study explored the effect of the 5-HTTLPR polymorphism in the serotonin transporter gene and adverse family environment on impulsivity in adolescents. Healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study (n=483) filled the Adaptive and Maladaptive Impulsivity Scale (AMIS), Barratt Impulsiveness Scale (BIS-11), a scale measuring family relations, and were genotyped. While genotype alone was not associated with thoughtlessness, BIS-11 impulsiveness, fast decision-making or excitement seeking, 5-HTTLPR S allele carriers, however, had higher scores of disinhibition. In girls carrying the S allele, scores of thoughtlessness and disinhibition depended on family relations, being higher with less warmth in the family. Adverse family relations had no effect on impulsivity in girls with LL genotype. In boys, the effects of family relations on maladaptive impulsivity did not depend on genotype. However, the S allele and high maltreatment in the family both independently increased disinhibition and the BIS-11 score in boys. Family environment and the 5-HTTLPR genotype had no interactive effect on excitement seeking or fast decision-making. In summary, carrying the S allele may lead to high maladaptive impulsivity due to higher sensitivity to environmental adversity, which is more significantly expressed in girls.

The clock gene PER2 and sleep problems: Association with alcohol consumption among Swedish adolescents

Abstract Background. Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. Previous studies have separately examined the effects of mutations in the clock gene PER2 on alcohol consumption and sleep problems. Here we hypothesized that an allelic variation in the PER2 gene is associated with alcohol consumption in interaction with sleep problems among adolescents. Methods. The Survey of Adolescent Life and Health in Västmanland 2006, a Swedish county, including 1254 students 17–18 years old, was used as a population-representative sample of adolescents. We investigated the PER2 Single Nucleotide polymorphism (SNP) 10870 (A/G) in the cohort together with an assessment of alcohol consumption according to the AUDIT-C questionnaire, and sleep problems using a survey consisting of 18 items. Furthermore, we carried out an exploratory analysis on the PER2 Single Nucleotide Polymorphism 10870 polymorphism in a group of severely alcoholic females. Results. We found a significant association of the SNP 10870 in adolescent boys, where the genotype AA, in the presence of several and frequent sleep problems, was associated with increased alcohol consumption. Among adolescent girls, only sleep problems were related to alcohol consumption. A non-significant trend was observed among the severely alcoholic females, with the G allele being over-represented in the severely alcoholic females group in comparision to the control females. Conclusion. These results indicate that PER2 gene variation is associated with alcohol consumption in interaction with sleep problems among Swedish adolescent boys.

Personality and the serotonin transporter gene: Associations in a longitudinal population-based study

Associations between the promoter polymorphism of the serotonin transporter gene (5-HTTLPR) and anxiety-related personality traits in healthy adult subjects have been inconsistent. We assessed personality in participants of the Estonian Children Personality Behaviour and Health Study, using parental reports and self-reports. In the younger cohort, according to parental assessments at ages 9 and 15, children homozygous for the S allele had significantly higher scores of Neuroticism and lower scores of Openness, Agreeableness and Conscientiousness. Parental assessment of the older cohort at ages 15 and 18 did not yield any genotype effect on personality; however, interaction of cohort and genotype was not significant. According to self-reports, SS homozygotes had higher Neuroticism at age 15 but not at age 18. Thus, homozygocity for the S allele of the 5-HTTLPR is related to anxiety-related personality traits in general population, but this is easier to detect before adolescence.

The impact of adverse life events and the serotonin transporter gene promoter polymorphism on the development of eating disorder symptoms

Adverse life events have been shown to predict weight fluctuations and dietary restraint, as well as eating disorders during adolescence or early adulthood. Since the s-allele carriers of the 5-HTT gene-linked polymorphic region (5-HTTLPR) are biologically more reactive to stress related stimuli, we aimed to explore whether the eating disturbances are predicted by environmental stressors and moderated by the 5-HTTLPR genotype. The sample was based on the younger cohort of the Estonian Children Personality, Behaviour and Health Study and included those participating in its second and third wave. The history of stressful life events was self-reported at age 15. Data on eating behaviour and attitudes, anxiety, impulsivity and depressiveness were collected at age 18. The effect of the adverse life events on binge eating and on drive for thinness was found to be moderated by the 5-HTTLPR. Adolescent girls who at age 15 had reported a history of frequent adverse life events had elevated scores in EDI-2 Bulimia subscale at age 18 if they were carrying the s-allele. The effect of the s-allele on binge eating was even more pronounced when solely the experience of sexual abuse was considered. The interaction effect of the 5-HTTLPR and the past sexual abuse was also observed on drive for thinness. These data give further support to the idea that adverse life events in childhood may heighten susceptibility to serotonergic dysregulation following stress, and suggest that in individuals vulnerable to eating disorders this may result in disturbed eating behaviours.