Susanne Henningsson

Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans

Pair-bonding has been suggested to be a critical factor in the evolutionary development of the social brain. The brain neuropeptide arginine vasopressin (AVP) exerts an important influence on pair-bonding behavior in voles. There is a strong association between a polymorphic repeat sequence in the 5′ flanking region of the gene (avpr1a) encoding one of the AVP receptor subtypes (V1aR), and proneness for monogamous behavior in males of this species. It is not yet known whether similar mechanisms are important also for human pair-bonding. Here, we report an association between one of the human AVPR1A repeat polymorphisms (RS3) and traits reflecting pair-bonding behavior in men, including partner bonding, perceived marital problems, and marital status, and show that the RS3 genotype of the males also affects marital quality as perceived by their spouses. These results suggest an association between a single gene and pair-bonding behavior in humans, and indicate that the well characterized influence of AVP on pair-bonding in voles may be of relevance also for humans.

A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

Sex steroid-related genes and male-to-female transsexualism.

Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and--after aromatase-catalyzed conversion to estradiol--via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERbeta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERbeta repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans

The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.

Serotonin transporter gene polymorphisms: Effect on serotonin transporter availability in the brain of suicide attempters

The efficacy of serotonin reuptake inhibitors in depression and anxiety disorders suggests the gene coding for the serotonin transporter (5-HTT), SLC6A4, as a candidate of importance for these conditions. Positive findings regarding associations between polymorphisms in SLC6A4 have been reported, indicating that these polymorphisms may influence anxiety-related personality traits, as well as the risk of developing depression and suicidality. Serotonin 5-HTT availability was assessed with single photon emission computed tomography (SPECT), using (123)I-beta-CIT as ligand, in a population of unmedicated male suicide attempters (n=9) and in matched controls (n=9). Two polymorphisms in SLC6A4 were assessed, including the 5-HTTLPR located in the promoter region and a variable number of tandem repeats (VNTR) polymorphism in intron 2 (STin2). In suicide attempters, but not in controls, low 5-HTT availability was associated with the S allele of 5-HTTLPR and with the 12 repeat allele of STin2. Data suggest that polymorphisms in SLC6A4 may influence the expression of the brain serotonin transporter in suicide attempters.

Genetic Variation in Brain-Derived Neurotrophic Factor Is Associated with Serotonin Transporter but Not Serotonin-1A Receptor Availability in Men

BACKGROUND The serotonergic system, including the serotonin transporter (5-HTT), which is the target of many antidepressants, seems to be influenced by brain-derived neurotrophic factor (BDNF). METHODS Positron emission tomography (PET) was used to address, in 25 and 53 healthy volunteers, respectively, the possible association between six polymorphisms in the gene encoding BDNF and the availability of two proteins expressed by serotonergic neurons: the 5-HTT, measured with the radioligand [(11)C]MADAM, and the serotonin-1A (5-HT1A) receptor, measured with [(11)C]WAY-100635. RESULTS Several single nucleotide polymorphisms were associated with [(11)C]MADAM binding potential (BP) in most brain regions, male carriers of the valine/valine genotype of the Val66Met polymorphism displaying higher availability. Effect sizes ranged from a 50% to a threefold increase. In contrast, there was no association for [(11)C]WAY-100635 BP. The observation that BDNF polymorphisms were associated with 5-HTT availability could be partly replicated in an independent population comprising nine male suicide attempters and nine matched control subjects, in which transporter availability had been measured with single photon emission computed tomography with (123)I-beta-CIT as ligand. CONCLUSIONS Our results suggest that genetic variation in BDNF influences 5-HTT but not 5-HT1A receptor density in the human brain.

Possible association between the androgen receptor gene and autism spectrum disorder

Autism is a highly heritable disorder but the specific genes involved remain largely unknown. The higher prevalence of autism in men than in women, in conjunction with a number of other observations, has led to the suggestion that prenatal brain exposure to androgens may be of importance for the development of this condition. Prompted by this hypothesis, we investigated the potential influence of variation in the androgen receptor (AR) gene on the susceptibility for autism. To this end, 267 subjects with autism spectrum disorder and 617 controls were genotyped for three polymorphisms in exon 1 of the AR gene: the CAG repeat, the GGN repeat and the rs6152 SNP. In addition, parents and affected siblings were genotyped for 118 and 32 of the cases, respectively. Case-control comparisons revealed higher prevalence of short CAG alleles as well as of the A allele of the rs6152 SNP in female cases than in controls, but revealed no significant differences with respect to the GGN repeat. Analysis of the 118 families using transmission disequilibrium test, on the other hand, suggested an association with the GGN polymorphism, the rare 20-repeat allele being undertransmitted to male cases and the 23-repeat allele being overtransmitted to female cases. Sequencing of the AR gene in 46 patients revealed no mutations or rare variants. The results lend some support for an influence of the studied polymorphisms on the susceptibility for autism, but argue against the possibility that mutations in the AR gene are common in subjects with this condition.

Interleukin-6 Gene Polymorphism −174G/C Influences Plasma Lipid Levels in Women

Elevated levels of the pro‐inflammatory cytokine interleukin‐6 (IL‐6) have been associated with cardiovascular risk factors. The objective of this study was to investigate potential associations between the promoter polymorphism IL‐6 −174G/C and the following indices of metabolism: BMI, waist‐to‐hip ratio, and plasma levels of IL‐6, cholesterol, low‐density lipoprotein, triglycerides, high‐density lipoprotein, leptin, and C‐reactive protein in 252 42‐year‐old women and 245 51‐year‐old men. Subgroups were also studied 5 years later. The CC genotype of the IL‐6 polymorphism was associated with lower levels of cholesterol and low‐density lipoprotein (p < 0.001) in women. This finding was replicated in the follow‐up, when a significant association between the CC genotype and low triglycerides was also observed. The association between the C allele and lipid pattern found in women was not found in men, where on the contrary, C carriers tended to display elevated triglycerides. IL‐6 genotype was not associated with IL‐6 plasma levels in either sample. The results suggest different effects of the IL‐6 polymorphism on metabolic indices in women and men. None of the associations between IL‐6 genotype and lipid pattern seemed to result from an effect of the polymorphism on IL‐6 plasma levels.

Further exploration of the possible influence of polymorphisms in HTR2C and 5HTT on body weight

Receptors of the 5-HT2C subtype are of importance for the influence of serotonin on food intake, and 2 single nucleotide polymorphisms in this gene (HTR2C)--Cys23Ser (rs6318) and -759C>T (rs3813929)--have been reported to be associated with weight and/or antipsychotic-induced weight gain. The present study aimed to replicate these associations; in addition, the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) was assessed. The polymorphisms were genotyped in subjects recruited from the normal population (n = 510), and possible associations between genotype and body mass index (BMI) were assessed. The Ser23 allele was more common in underweight subjects (BMI <20) than in normal- and overweight (BMI > or =20) subjects (P = .006). The T allele of the -759C/T polymorphism was less common in the overweight group (BMI > or =25) (P = .007). Homozygosity for the short allele of 5-HTTLPR was more frequent in underweight subjects (P = .015). Our results are in agreement with previous studies, suggesting polymorphisms in HTR2C to be associated with body weight, particularly in women; and they also suggest that 5-HTTLPR may influence this phenotype. Further studies on the importance of the investigated genes for eating disorders and drug-induced weight gain are warranted.

Association between serum levels of C-reactive protein and personality traits in women

BackgroundWhile low-grade inflammation has consistently been observed in subjects with depression, studies on the possible relationship between inflammation and other aspects of brain function are as yet sparse. In this study, we aimed to investigate the possible association between serum levels of the inflammation marker C-reactive protein (CRP) and personality traits.MethodsIn this study, serum levels of high-sensitivity CRP were determined by ELISA in a population of 270 42-year-old women recruited from the population registry who had been assessed using the Temperament and Character Inventory. Self-reported previous or ongoing depression was also recorded. Unpaired two-tailed t-tests were used for comparison between two groups and correlations were evaluated by the calculation of Pearsons r-coefficient.ResultsThe temperament trait harm avoidance was positively (r = 0.227, p < 0.05) and the character trait self-directedness was negatively (r = -0.261, p < 0.01) associated with serum levels of CRP (p-values corrected for multiple comparisons). The correlations between the personality traits and CRP were observed also after exclusion of subjects reporting ongoing depression (n = 26). Whereas women reporting ongoing depression showed significantly increased levels of CRP as compared to non-depressed women (n = 155), women reporting a history of depression displayed no significant difference in CRP levels as compared to women that reported that they had never been depressed.ConclusionSerum levels of CRP in women was found to be associated with the personality traits harm avoidance and self-directedness. In addition, moderately elevated levels may be a state dependent marker of depression.