Sami Pirkola

Childhood Adversities Are Associated with Shorter Telomere Length at Adult Age both in Individuals with an Anxiety Disorder and Controls

Accelerated leukocyte telomere shortening has been previously associated to self-perceived stress and psychiatric disorders, including schizophrenia and mood disorders. We set out to investigate whether telomere length is affected in patients with anxiety disorders in which stress is a known risk factor. We also studied the effects of childhood and recent psychological distress on telomere length. We utilized samples from the nationally representative population-based Health 2000 Survey that was carried out between 2000–2001 in Finland to assess major public health problems and their determinants. We measured the relative telomere length of the peripheral blood cells by quantitative real-time PCR from 321 individuals with DSM-IV anxiety disorder or subthreshold diagnosis and 653 matched controls aged 30–87 years, who all had undergone the Composite International Diagnostic Interview. While telomere length did not differ significantly between cases and controls in the entire cohort, the older half of the anxiety disorder patients (48–87 years) exhibited significantly shorter telomeres than healthy controls of the same age (P = 0.013). Interestingly, shorter telomere length was also associated with a greater number of reported childhood adverse life events, among both the anxiety disorder cases and controls (P = 0.005). Childhood chronic or serious illness was the most significantly associated single event affecting telomere length at the adult age (P = 0.004). Self-reported current psychological distress did not affect telomere length. Our results suggest that childhood stress might lead to accelerated telomere shortening seen at the adult age. This finding has potentially important implications supporting the view that childhood adversities might have a considerable impact on well being later in life.

Community mental-health services and suicide rate in Finland: a nationwide small-area analysis

BACKGROUND In many countries, psychiatric services have been reformed by reducing the size of hospitals and developing community mental-health services. We investigated this reform by assessing the relation between suicide risk and different ways of organising mental-health services. METHODS We did a nationwide comprehensive survey of Finnish adult mental-health service units between Sept 1, 2004, and March 31, 2005. From health-care or social-care officers of 428 municipalities, we asked for information, classified according to the European service mapping schedule, about adult mental-health services. For each municipality, we measured age-adjusted and sex-adjusted suicide risk, pooled between 2000 and 2004, and then adjusted for register-derived socioeconomic factors. FINDINGS A wide variety of outpatient services (relative risk [RR] 0.92, 95% CI 0.87-0.96), prominence of outpatient versus inpatient services (0.93, 0.89-0.97), and 24-h emergency services (0.84, 0.75-0.92) were associated with decreased death rates from suicide. However, after adjustment for socioeconomic factors, only the prominence of outpatient services was associated with low suicide rate (0.94, 0.90-0.98). We replicated this finding even after adjustment for organisational changes and inpatient treatment. INTERPRETATION Well-developed community mental-health services are associated with lower suicide rates than are services oriented towards inpatient treatment provision. These data are consistent with the idea that population mental health can be improved by use of multifaceted, community-based, specialised mental-health services. FUNDING Academy of Finland.

Systematic Analysis of Circadian Genes in a Population-Based Sample Reveals Association of TIMELESS with Depression and Sleep Disturbance

Disturbances in the circadian pacemaker system are commonly found in individuals with depression and sleep-related problems. We hypothesized that some of the canonical circadian clock genes would be associated with depression accompanied by signs of disturbed sleep, early morning awakening, or daytime fatigue. We tested this hypothesis in a population-based sample of the Health 2000 dataset from Finland, including 384 depressed individuals and 1270 controls, all with detailed information on sleep and daytime vigilance, and analyzed this set of individuals with regard to 113 single-nucleotide polymorphisms of 18 genes of the circadian system. We found significant association between TIMELESS variants and depression with fatigue (D+FAT+) (rs7486220: pointwise P = 0.000099, OR = 1.66; corrected empirical P for the model of D+FAT+  = 0.0056; haplotype ‘C-A-A-C’ of rs2291739-rs2291738-rs7486220-rs1082214: P = 0.0000075, OR = 1.72) in females, and association to depression with early morning awakening (D+EMA+) (rs1082214: pointwise P = 0.0009, OR = 2.70; corrected empirical P = 0.0374 for the model D+EMA+; haplotype ‘G-T’ of rs7486220 and rs1082214: P = 0.0001, OR = 3.01) in males. There was significant interaction of gender and TIMELESS (for example with rs1082214, P = 0.000023 to D+EMA+ and P = 0.005 to D+FAT+). We obtained supported evidence for involvement of TIMELESS in sleeping problems in an independent set of control individuals with seasonal changes in mood, sleep duration, energy level and social activity in females (P = 0.036, ® = 0.123 for rs1082214) and with early morning awakening or fatigue in males (P = 0.038 and P = 0.0016, respectively, for rs1082214). There was also some evidence of interaction between TIMELESS and PER1 in females to D+FAT+ as well as between TIMELESS and ARNTL, RORA or NR1D1 in males to D+EMA+. These findings support a connection between circadian genes and gender-dependent depression and defective sleep regulation.

Circadian Clock Gene Polymorphisms in Alcohol Use Disorders and Alcohol Consumption

AIMS Circadian clock genes are involved in the development of drug-induced behaviors and regulate neurotransmission pathways in addiction. Our aim was to study whether circadian clock gene polymorphisms predispose to alcohol dependence or abuse or other alcohol-related characteristics. METHODS The study sample comprised of 512 individuals having alcohol dependence or alcohol abuse (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)) and their 511 age- and sex-matched controls. This population-based sample was drawn from a cohort (n = 7415), representative of the Finnish general population aged 30 and over. Altogether 42 single-nucleotide polymorphisms of 19 genes related to the circadian pacemaker system were genotyped. RESULTS ARNTL rs6486120 T(+) allelic status (P = 0.0007, q = 0.17), ADCYAP1 rs2856966 GG genotype (P = 0.0006, q = 0.17) and VIP CC haplotype (rs3823082-rs688136) (P = 0.0006) were suggestively associated with alcohol consumption in socially drinking controls. ARNTL2 GT haplotype (rs7958822-rs4964057) associated suggestively with alcohol abuse diagnosis (P = 0.0013). Earlier findings on the associations of DRD2 and NPY with alcohol dependence were supported: DRD2/ANKK1 Taq1A(1) increased (P = 0.04) and NPY Pro7 decreased (P = 0.01) the risk of alcohol dependence. CONCLUSIONS ARNTL, ARNTL2, VIP and ADCYAP1 were indicated as having influence on alcohol use or abuse. The role of DRD2 and NPY on alcohol dependence was also supported.

An Association Analysis of Circadian Genes in Anxiety Disorders

BACKGROUND The mammalian circadian system is responsible for controlling daily oscillations in physiology and behavior. Circadian genes contribute to the sleep-wake cycle and mood, and because patients with anxiety disorder often suffer from sleep disturbances, we hypothesized that variants in circadian-clock-related genes might predispose to human anxiety disorders as well. We tested this hypothesis with a genetic association analysis. METHODS We analyzed 131 single nucleotide polymorphisms from 13 circadian-clock-related genes. The study sample consisted of 321 individuals diagnosed with an anxiety disorder and 653 matched healthy controls from a Finnish population-based cohort. RESULTS Single nucleotide polymorphisms in two genes showed some evidence for association to social phobia: in ARNTL2 rs2306073 (p = .0099) and in DRD2 rs7131056 (p = .0084). BCL2 rs12454712 (p = .0029) and DRD2 rs4245146 (p = .0010) showed evidence for association to generalized anxiety disorder, whereas rs2463107 (p = .0064) in PAWR and rs4245146 (p = .0029) in DRD2 showed evidence for association to the pooled group of all anxiety disorders. Findings in DRD2 became stronger when only anxiety disorder cases with comorbid alcohol use disorder were considered. CONCLUSIONS Genes contributing to circadian rhythms might also play a role in the genetic predisposition to anxiety disorders. In addition, our study provides further support for the association of DRD2 to comorbid anxiety and alcohol use disorder.

Assessment of the neuropeptide S system in anxiety disorders

BACKGROUND The G protein-coupled receptor neuropeptide S receptor 1 (NPSR1) and its ligand neuropeptide S (NPS) form a signaling system mainly implicated in susceptibility to asthma and inflammatory disorders in humans and regulation of anxiety and arousal in rodents. We addressed here the role of NPS and NPSR1 as susceptibility genes for human anxiety disorders. METHODS We performed comprehensive association analysis of genetic variants in NPS and NPSR1 in three independent study samples. We first studied a population-based sample (Health 2000, Finland) of 321 anxiety disorder patients and 1317 control subjects and subsequently a Spanish clinical panic disorder sample consisting of 188 cases and 315 control subjects. In addition, we examined a birth cohort of 2020 children (Barn Allergi Miljö Stockholm Epidemiologi [BAMSE], Sweden). We then tested whether alleles of the most significantly associated single nucleotide polymorphisms alter DNA-protein complex formation in electrophoretic mobility shift assays. Finally, we compared acute stress responses on the gene expression level in wild-type and Npsr1(-/-) mice. RESULTS We confirmed previously observed epidemiological association between anxiety and asthma in two population-based cohorts. Single nucleotide polymorphisms within NPS and NPSR1 associated with panic disorder diagnosis in the Finnish and Spanish samples and with parent-reported anxiety/depression in the BAMSE sample. Moreover, some of the implicated single nucleotide polymorphisms potentially affect transcription factor binding. Expression of neurotrophin-3, a neurotrophic factor connected to stress and panic reaction, was significantly downregulated in brain regions of stressed Npsr1(-/-) mice, whereas interleukin-1 beta, an active stress-related immunotransmitter, was upregulated. CONCLUSIONS Our results suggest that NPS-NPSR1 signaling is likely involved in anxiety.

A Population-Based Association Study of Candidate Genes for Depression and Sleep Disturbance

The clinical manifestation of depression comprises a variety of symptoms, including early morning awakenings and fatigue, features also indicating disturbed sleep. The presence or absence of these symptoms may reflect differences in neurobiological processes leading to prolonged depression. Several neurobiological mechanisms have been indicated in the induction of depression, including disturbances in serotonergic and glutamatergic neurotransmission and in the action of the hypothalamic–pituitary–adrenal (HPA) axis. The same transmitters have also been linked to sleep regulation. We hypothesized that depression without simultaneous symptoms of disturbed sleep would partly have a different genetic background than depression with symptoms of disturbed sleep. We tested this hypothesis using a systematic population‐based association study of 14 candidate genes related to depression and disturbed sleep. Association of genetic variants with either depression alone, depression with early morning awakenings, or depression with fatigue was investigated using permutation‐based allelic association analysis of a sample of 1,654 adults recruited from Finlands population‐based program. The major findings were associations of TPH2 (rs12229394) with depression accompanied by fatigue in women and CREB1 (rs11904814) with depression alone in men. We also found suggestive associations in women for GAD1, GRIA3, and BDNF with depression accompanied by fatigue, and for CRHR1 with depression accompanied by early morning awakenings. The results indicate sex‐dependent and symptom‐specific differences in the genetic background of depression. These differences may partially explain the broad spectrum of depressive symptoms, and their systematic monitoring could potentially be used for diagnostic purposes.

Type 2 diabetes among persons with schizophrenia and other psychotic disorders in a general population survey

Schizophrenia and other psychotic disorders are associated with increased risk of developing type 2 diabetes. However, previous studies are mainly based on clinical samples where the comorbidity may be stronger. We investigated in a general population survey the prevalence of type 2 diabetes in persons with psychotic disorders and in users of antipsychotic medication. The study was based on a nationally representative two-stage cluster sample of 8,028 persons aged 30 or over from Finland. Diagnostic assessment of psychotic disorders combined SCID-I interview and case note data. Prevalences of type 2 diabetes, adjusting for age and sex, were estimated by calculating predicted marginals. The prevalence estimate of type 2 diabetes was 22.0% among subjects with schizophrenia, 13.4% among subjects with other nonaffective psychosis and 6.1% in subjects without psychotic disorders. Only two subjects (3.4%) with affective psychosis had type 2 diabetes. Users of all types of antipsychotic medication had increased prevalence of type 2 diabetes. Our results suggest that type 2 diabetes is a major health concern among persons with schizophrenia and other nonaffective psychotic disorders and also in users of antipsychotic medication, but persons with affective psychosis in the general population may not have increased prevalence of type 2 diabetes.

An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders.

Background Human anxiety disorders are complex diseases with largely unknown etiology. We have taken a cross-species approach to identify genes that regulate anxiety-like behavior with inbred mouse strains that differ in their innate anxiety levels as a model. We previously identified 17 genes with expression levels that correlate with anxiety behavior across the studied strains. In the present study, we tested their 13 known human homologues as candidate genes for human anxiety disorders with a genetic association study. Methods We describe an anxiety disorder study sample derived from a Finnish population-based cohort and consisting of 321 patients and 653 carefully matched control subjects, all interviewed to obtain DSM-IV diagnoses. We genotyped altogether 208 single nucleotide polymorphisms (SNPs) (all non-synonymous SNPs, SNPs that alter potential microRNA binding sites, and gap-filling SNPs selected on the basis of HapMap information) from the investigated anxiety candidate genes. Results Specific alleles and haplotypes of six of the examined genes revealed some evidence for association (p ≤ .01). The most significant evidence for association with different anxiety disorder subtypes were: p = .0009 with ALAD (δ-aminolevulinate dehydratase) in social phobia, p = .009 with DYNLL2 (dynein light chain 2) in generalized anxiety disorder, and p = .004 with PSAP (prosaposin) in panic disorder. Conclusions Our findings suggest that variants in these genes might predispose to specific human anxiety disorders. These results illustrate the potential utility of cross-species approaches in identification of candidate genes for psychiatric disorders.

Contribution of adenosine related genes to the risk of depression with disturbed sleep

BACKGROUND Most patients with major depression report problems in their sleep: insomnia, early morning awakenings and fatigue correlating with poor sleep quality. One of the key substances regulating sleep is adenosine. We hypothesized that variations in polymorphic sites of adenosine related genes may predispose to depression with sleep disturbances. METHODS We selected 117 single nucleotide polymorphisms from 13 genes and analyzed their association with depression and specific sleep problems (early morning awakenings and fatigue). Data were collected as part of the Health 2000 Study based on Finnish population and included 1423 adult subjects. RESULTS Our major finding herein was, among women, the association of SLC29A3 polymorphism rs12256138 with depressive disorder (p=0.0004, odds ratio=0.68, 95% CI 0.55-0.84, p<0.05 after Bonferonni correction for multiple testing). Only one gene showing any evidence for association was common to women and men (ADA). LIMITATIONS Relatively small size of the case samples. CONCLUSIONS Our results suggest that compromised adenosine transport due to variation in nucleoside transporter gene SLC29A3 in women, could predispose to depression, and could suggest new directions in treatment research. The shortage of overlapping genes between the genders indicates that the genetics of mood regulation may vary between the sexes.