Hippocampal volume changes in a pharmacological sex-hormone manipulation risk model for depression in women.

Hormone transition phases may trigger depression in some women, yet the underlying mechanisms remain elusive. In a pharmacological sex-hormone manipulation model, we previously reported that estradiol reductions, induced with a gonadotropin-releasing hormone agonist (GnRHa), provoked subclinical depressive symptoms in healthy women, especially if neocortical serotonin transporter (SERT) binding also increased. Within this model, we here evaluated if GnRHa, compared to placebo, reduced hippocampal volume, in a manner that depended on the magnitude of the estradiol decrease and SERT binding, and if this decrease translated to the emergence of subclinical depressive symptoms. Sixty-three healthy, naturally cycling women were included in a randomized, double-blind, placebo-controlled GnRHa-intervention study. We quantified the change from baseline to follow-up (n = 60) in serum estradiol (ΔEstradiol), neocortical SERT binding ([11C] DASB positron emission tomography; ΔSERT), subclinical depressive symptoms (Hamilton depression rating scale; ΔHAMD-17), and hippocampal volume (magnetic resonance imaging data analyzed in Freesurfer 7.1, ΔHippocampus). Group differences in ΔHippocampus were evaluated in a t-test. Within the GnRHa group, associations between ΔEstradiol, ΔHippocampus, and ΔHAMD-17, in addition to ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus, were evaluated with linear regression models. Mean ΔHippocampus was not significantly different between the GnRHa and placebo group. Within the GnRHa group, hippocampal volume reductions were associated with the magnitude of estradiol decrease (p = 0.04, Cohen's f2 = 0.18), controlled for baseline SERT binding, but not subclinical depressive symptoms. There was no ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus. If replicated, our data highlight a possible association between estradiol fluctuations and hippocampal plasticity, adjusted for serotonergic contributions.

A randomized placebo-controlled intranasal oxytocin study on first impressions and reactions to social rejection.

Oxytocin is central to pair-bonding in non-human animals. We assessed effects of intranasal oxytocin on bond formation between two opposite-sex strangers. In a double-blind placebo-controlled design, 50 pairs of one man and one woman received oxytocin or placebo spray intranasally. After treatment, they played a social interaction game, followed by tasks designed to measure first impressions of the opposite-sex co-participant, and a virtual ball-tossing game (cyberball), designed to measure reactions to rejection by the co-participant. We found no evidence that intranasal oxytocin can improve first impressions of an opposite-sex stranger, and some Bayesian support against this hypothesis. For rejection sensitivity, we observed a sex-and-context-dependent drug effect on post-ostracism mood ratings, consistent with recent studies indicating that interindividual variation and social context can interact with intranasal oxytocin effects. Further research is needed to determine the generalisability of these findings, i.e. if oxytocin can improve first impressions in humans under different conditions.

Emotion recognition associated with polymorphism in oxytocinergic pathway gene ARNT2.

The ability to correctly understand the emotional expression of another person is essential for social relationships and appears to be a partly inherited trait. The neuropeptides oxytocin and vasopressin have been shown to influence this ability as well as face processing in humans. Here, recognition of the emotional content of faces and voices, separately and combined, was investigated in 492 subjects, genotyped for 25 single nucleotide polymorphisms (SNPs) in eight genes encoding proteins important for oxytocin and vasopressin neurotransmission. The SNP rs4778599 in the gene encoding aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), a transcription factor that participates in the development of hypothalamic oxytocin and vasopressin neurons, showed an association that survived correction for multiple testing with emotion recognition of audio-visual stimuli in women (n = 309). This study demonstrates evidence for an association that further expands previous findings of oxytocin and vasopressin involvement in emotion recognition.

Pharmacologically Induced Sex Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression: A Randomized Trial.

Women are at relatively greater lifetime risk for depression than men. This elevated risk in women is partly due to heightened risk during time periods characterized by marked fluctuations in sex hormones, including postpartum and perimenopausal periods. How sex hormone fluctuations contribute to heightened risk is not fully understood but may involve intrinsic functional connectivity. We induced a biphasic ovarian sex hormone fluctuation using the gonadotropin-releasing hormone agonist (GnRHa) goserelin to determine, with a randomized placebo-controlled design, intervention effects on or GnRHa-provoked depressive symptoms associations with change in resting-state functional connectivity (rs-FC) in 58 healthy women for six seeds (amygdala, hippocampus, anterior cingulate cortex, dorsal raphe, median raphe, and posterior cingulate cortex). GnRHa intervention did not significantly affect rs-FC in any seeds. Considering the GnRHa group only, the emergence of depressive symptoms following intervention was positively associated with amygdala-right temporal cortex and negatively associated with hippocampus-cingulate rs-FC. A test for mediation suggested that rs-FC changes in these networks marginally mediated the association between decrease in estradiol and increase in depressive symptoms in the GnRHa group (p=0.07). Our findings provide novel evidence-linking changes in rs-FC networks, the emergence of depressive symptoms and sex hormone fluctuations. Notably, we observed evidence that changes in rs-FC may represent a key neurobiological intermediary between molecular changes induced by hormone fluctuations and the emergence of depressive symptoms. Taken together, our findings indicate that sex hormone fluctuations may contribute to heightened risk for developing depressive symptoms by affecting intrinsic functional connectivity of key limbic brain structures.

Variation in the Oxytocin Receptor Gene Is Associated with Face Recognition and its Neural Correlates.

The ability to recognize faces is crucial for daily social interactions. Recent studies suggest that intranasal oxytocin administration improves social recognition in humans. Oxytocin signaling in the amygdala plays an essential role for social recognition in mice, and oxytocin administration has been shown to influence amygdala activity in humans. It is therefore possible that the effects of oxytocin on human social recognition depend on mechanisms that take place in the amygdala-a central region for memory processing also in humans. Variation in the gene encoding the oxytocin receptor (OXTR) has been associated with several aspects of social behavior. The present study examined the potential associations between nine OXTR polymorphisms, distributed across the gene, and the ability to recognize faces, as well as face-elicited amygdala activity measured by functional magnetic resonance imaging (fMRI) during incidental encoding of faces. The OXTR 3' polymorphism rs7632287, previously related to social bonding behavior and autism risk, was associated with participants' ability to recognize faces. Carriers of the GA genotype, associated with enhanced memory, displayed higher amygdala activity during face encoding compared to carriers of the GG genotype. In line with work in rodents, these findings suggest that, in humans, naturally occurring endogenous modulation of OXTR function affects social recognition through an amygdala-dependent mechanism. These findings contribute to the understanding of how oxytocin regulates human social behaviors.

Serotonergic neurotransmission in emotional processing: New evidence from long-term recreational poly-drug ecstasy use.

The brain's serotonergic system plays a crucial role in the processing of emotional stimuli, and several studies have shown that a reduced serotonergic neurotransmission is associated with an increase in amygdala activity during emotional face processing. Prolonged recreational use of ecstasy (3,4-methylene-dioxymethamphetamine [MDMA]) induces alterations in serotonergic neurotransmission that are comparable to those observed in a depleted state. In this functional magnetic resonance imaging (fMRI) study, we investigated the responsiveness of the amygdala to emotional face stimuli in recreational ecstasy users as a model of long-term serotonin depletion. Fourteen ecstasy users and 12 non-using controls underwent fMRI to measure the regional neural activity elicited in the amygdala by male or female faces expressing anger, disgust, fear, sadness, or no emotion. During fMRI, participants made a sex judgement on each face stimulus. Positron emission tomography with 11C-DASB was additionally performed to assess serotonin transporter (SERT) binding in the brain. In the ecstasy users, SERT binding correlated negatively with amygdala activity, and accumulated lifetime intake of ecstasy tablets was associated with an increase in amygdala activity during angry face processing. Conversely, time since the last ecstasy intake was associated with a trend toward a decrease in amygdala activity during angry and sad face processing. These results indicate that the effects of long-term serotonin depletion resulting from ecstasy use are dose-dependent, affecting the functional neural basis of emotional face processing.

Social memory associated with estrogen receptor polymorphisms in women.

The ability to recognize the identity of faces and voices is essential for social relationships. Although the heritability of social memory is high, knowledge about the contributing genes is sparse. Since sex differences and rodent studies support an influence of estrogens and androgens on social memory, polymorphisms in the estrogen and androgen receptor genes (ESR1, ESR2, AR) are candidates for this trait. Recognition of faces and vocal sounds, separately and combined, was investigated in 490 subjects, genotyped for 10 single nucleotide polymorphisms (SNPs) in ESR1, four in ESR2 and one in the AR Four of the associations survived correction for multiple testing: women carrying rare alleles of the three ESR2 SNPs, rs928554, rs1271572 and rs1256030, in linkage disequilibrium with each other, displayed superior face recognition compared with non-carriers. Furthermore, the uncommon genotype of the ESR1 SNP rs2504063 was associated with better recognition of identity through vocal sounds, also specifically in women. This study demonstrates evidence for associations in women between face recognition and variation in ESR2, and recognition of identity through vocal sounds and variation in ESR1. These results suggest that estrogen receptors may regulate social memory function in humans, in line with what has previously been established in mice.

Sex-Steroid Hormone Manipulation Reduces Brain Response to Reward.

Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo or the gonadotropin-releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex-steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary rewards. There was a positive association between the individual changes in testosterone and changes in bilateral insula response to monetary rewards. Our data provide evidence for the involvement of sex-steroid hormones in reward processing. A blunted amygdala response to rewarding stimuli following a rapid decline in sex-steroid hormones may reflect a reduced engagement in positive experiences. Abnormal reward processing may constitute a neurobiological mechanism by which sex-steroid fluctuations provoke mood disorders in susceptible women.

The Center for Integrated Molecular Brain Imaging (Cimbi) database.

We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes. The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies. The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank.

Association between polymorphisms in NOS3 and KCNH2 and social memory.

Social memory, including the ability to recognize faces and voices, is essential for social relationships. It has a large heritable component, but the knowledge about the contributing genes is sparse. The genetic variation underlying inter-individual differences in social memory was investigated in an exploratory sample (n = 55), genotyped with a chip comprising approximately 200,000 single nucleotide polymorphisms (SNPs), and in a validation sample (n = 582), where 30 SNPs were targeted. In the exploratory study face identity recognition was measured. The validation study also measured vocal sound recognition, as well as recognition of faces and vocal sounds combined (multimodal condition). In the exploratory study, the 30 SNPs that were associated with face recognition at p uncorrected < 0.001 and located in genes, were chosen for further study. In the validation study two of these SNPs showed significant associations with recognition of faces, vocal sounds, and multimodal stimuli: rs1800779 in the gene encoding nitric oxide synthase 3 (NOS3) and rs3807370 in the gene encoding the voltage-gated channel, subfamily H, member 2 (KCNH2), in strong linkage disequilibrium with each other. The uncommon alleles were associated with superior performance, and the effects were present for men only (p < 0.0002). The exploratory study also showed a weaker but significant association with (non-emotional) word recognition, an effect that was independent of the effect on face recognition. This study demonstrates evidence for an association between NOS3 and KCNH2 SNPs and social memory.

Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study.

BACKGROUND: An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS: A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). RESULTS: Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003). CONCLUSIONS: Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.

Amygdala signals subjective appetitiveness and aversiveness of mixed gambles.

People are more sensitive to losses than to equivalent gains when making financial decisions. We used functional magnetic resonance imaging (fMRI) to illuminate how the amygdala contributes to loss aversion. The blood oxygen level dependent (BOLD) response of the amygdala was mapped while healthy individuals were responding to 50/50 gambles with varying potential gain and loss amounts. Overall, subjects demanded twice as high potential gain as loss to accept a gamble. The individual level of loss aversion was expressed by the decision boundary, i.e., the gain-loss ratio at which subjects accepted and rejected gambles with equal probability. Amygdala activity increased the more the gain-loss ratio deviated from the individual decision boundary showing that the amygdala codes action value. This response pattern was more strongly expressed in loss aversive individuals, linking amygdala activity with individual differences in loss aversion. Together, the results show that the amygdala signals subjective appetitiveness or aversiveness of gain-loss ratios at the time of choice.

Variation in the oxytocin receptor gene is associated with behavioral and neural correlates of empathic accuracy.

The neuromodulators oxytocin and serotonin have been implicated in regulating affective processes underlying empathy. Understanding this dependency, however, has been limited by a lack of objective metrics for measuring empathic performance. Here we employ a novel psychophysical method for measuring empathic performance that quantitatively measures the ability of subjects to decode the experience of another person's pain. In 50 female subjects, we acquired functional magnetic resonance imaging data as they were exposed to a target subject experiencing variable degrees of pain, whilst performing an irrelevant attention-demanding task. We investigated the effect of variation in the oxytocin receptor gene (OXTR) and the serotonin transporter gene (SLC6A4) on the psychophysical and neurometric variability associated with empathic performance. The OXTR rs2268498 and rs53576 polymorphisms, but not the SLC6A4 5-HTTLPR, were associated with significant differences in empathic accuracy, with CC- and AA-carriers, respectively, displaying higher empathic accuracy. For OXTR rs2268498 there was also a genotype difference in the correlation between empathic accuracy and activity in the superior temporal sulcus (STS). In OXTR rs2268498 CC-carriers, high empathic accuracy was associated with stronger responsiveness of the right STS to the observed pain. Together, the results show that genetic variation in the OXTR has significant influence on empathic accuracy and that this may be linked to variable responsivity of the STS.

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.

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.

Influence of androgen receptor repeat polymorphisms on personality traits in men.

BACKGROUND: Testosterone has been attributed importance for various aspects of behaviour. The aim of our study was to investigate the potential influence of 2 functional polymorphisms in the amino terminal of the androgen receptor on personality traits in men. METHODS: We assessed and genotyped 141 men born in 1944 recruited from the general population. We used 2 different instruments: the Karolinska Scales of Personality and the Temperament and Character Inventory. For replication, we similarly assessed 63 men recruited from a forensic psychiatry study group. RESULTS: In the population-recruited sample, the lengths of the androgen receptor repeats were associated with neuroticism, extraversion and self-transcendence. The association with extraversion was replicated in the independent sample. LIMITATIONS: Our 2 samples differed in size; sample 1 was of moderate size and sample 2 was small. In addition, the homogeneity of sample 1 probably enhanced our ability to detect significant associations between genotype and phenotype. CONCLUSION: Our results suggest that the repeat polymorphisms in the androgen receptor gene may influence personality traits in men.

Genotype over-diagnosis in amygdala responsiveness: affective processing in social anxiety disorder.

BACKGROUND: Although the amygdala is thought to be a crucial brain region for negative affect, neuroimaging studies do not always show enhanced amygdala response to aversive stimuli in patients with anxiety disorders. Serotonin (5-HT)-related genotypes may contribute to interindividual variability in amygdala responsiveness. The short (s) allele of the 5-HT transporter linked polymorphic region (5-HTTLPR) and the T variant of the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene have previously been associated with amygdala hyperresponsivity to negative faces in healthy controls. We investigated the influence of these polymorphisms on amygdala responsiveness to angry faces in patients with social anxiety disorder (SAD) compared with healthy controls. METHODS: We used positron emission tomography with oxygen 15-labelled water to assess regional cerebral blood flow in 34 patients with SAD and 18 controls who viewed photographs of angry and neutral faces presented in counterbalanced order. We genotyped all participants with respect to the 5-HTTLPR and TPH2 polymorphisms. RESULTS: Patients with SAD and controls had increased left amygdala activation in response to angry compared with neutral faces. Genotype but not diagnosis explained a significant portion of the variance in amygdala responsiveness, the response being more pronounced in carriers of s and/or T alleles. LIMITATIONS: Our analyses were limited owing to the small sample and the fact that we were unable to match participants on genotype before enrollment. In addition, other imaging techniques not used in our study may have revealed additional effects of emotional stimuli. CONCLUSION: Amygdala responsiveness to angry faces was more strongly related to serotonergic polymorphisms than to diagnosis of SAD. Emotion activation studies comparing amygdala excitability in patient and control groups could benefit from taking variation in 5-HT-related genes into account.

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.

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.

Association between the AGTR1 polymorphism +1166A>C and serum levels of high-sensitivity C-reactive protein.

Genetic factors have been shown to influence high-sensitivity C-reactive protein (hsCRP) levels, however, which genes that are involved in this process remains to be clarified. The renin-angiotensin system (RAS) is of importance for the regulation of inflammation, and blockade of angiotensin II type 1 receptors (AGTR1) influences hsCRP levels. These findings prompted us to investigate whether a polymorphism in the AGTR1 gene may influence hsCRP levels. Additionally, a polymorphism in the CRP gene that has previously been shown to influence hsCRP levels was genotyped. Serum levels of hsCRP were measured in 270 42-year-old women recruited from the population registry. Two single nucleotide polymorphisms were analysed: +1166A>C and +1444C>T of the AGTR1 and CRP gene, respectively. The A allele of the AGTR1 polymorphism +1166A>C was dose-dependently associated with higher hsCRP levels (p=0.014, adjusted for confounding factors and multiple comparisons). hsCRP levels were not significantly influenced by the CRP +1444C>T genotype; however, an interaction between the two studied polymorphisms with respect to hsCRP levels was observed (p=0.018). The significant association between the AGTR1 polymorphism and hsCRP levels, which appears to be independent of anthropometric and metabolic traits, is yet another indication of a direct influence of RAS on inflammation.