Martin Tesli

A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample

BACKGROUND In the present study we investigated genetic variants associated with bipolar disorder in a homogenous Norwegian sample, and potential genetic overlap with schizophrenia, using the Affymetrix 6.0 array. METHODS We carried out a genome-wide association study (GWAS) by genotyping 620 390 single-nucleotide polymorphisms (SNPs) in a case-control sample of Norwegian origin (the TOP study) including bipolar disorder (n=194), healthy controls (n=336) and schizophrenia (n=230), followed by replication and combined analysis in a genetically concordant Icelandic sample of bipolar disorder (n=435), and healthy controls (n=10,258). RESULTS We selected 1000 markers with the lowest P values in the TOP discovery GWAS and tested these (or their surrogates) for association in the Icelandic replication sample. Polymorphisms on 35 loci were confirmed associated with bipolar disorder (nominal P value<0.05; not corrected for multiple testing) in the replication sample. The most significant markers were located in DLEU2, GUCY1B2, PKIA, CCL2, CNTNAP5, DPP10, and FBN1. The combined group of schizophrenia and bipolar disorder compared to controls did not provide additional significant findings. LIMITATIONS Relatively small number of samples. CONCLUSIONS We detected weak but reproducible association with markers in several genes, in proximity to susceptibility loci found in previous GWAS studies of bipolar disorder. Further work is required to study their localization, expression, and regulation and international meta-analytic efforts will help to further elucidate their role.

BDNF val66met modulates the association between childhood trauma, cognitive and brain abnormalities in psychoses

OBJECTIVE Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. METHOD 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean±age: 30.7±10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n=106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean±age: 32.67±10.85; 49% males) had data on sMRI. RESULTS Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r(2)=0.43; p=0.008), and larger right and left lateral ventricles (r(2)=0.37; p=0.002, and r(2)=0.27; p=0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. CONCLUSION Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups.

CACNA1C risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls

Objectives Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups. Methods Rs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group. Results In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups. Conclusions These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.

TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders.

TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n=596) and healthy controls (n=385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment.

Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

Polygenic Risk for Schizophrenia Associated With Working Memory-related Prefrontal Brain Activation in Patients With Schizophrenia and Healthy Controls

Schizophrenia is a highly heritable and polygenic disease, and identified common genetic variants have shown weak individual effects. Many studies have reported altered working memory (WM)-related brain activation in schizophrenia, preferentially in the frontal lobe. Such differences in brain activations could reflect inherited alterations possibly involved in the disease etiology, or rather secondary disease-related mechanisms. The use of polygenic risk scores (PGRS) based on a large number of risk polymorphisms with small effects is a valuable approach to examine the effect of cumulative genetic risk on brain functioning. This study examined the impact of cumulative genetic risk for schizophrenia on WM-related brain activations, assessed with functional magnetic resonance imaging. For each participant (63 schizophrenia patients and 118 healthy controls), we calculated a PGRS for schizophrenia based on 18 862 single-nucleotide polymorphism in a large multicenter genome-wide association study including 9146 schizophrenia patients and 12 111 controls, performed by the Psychiatric Genomics Consortium. As expected, the PGRS was significantly higher in patients compared with healthy controls. Further, the PGRS was related to differences in frontal lobe brain activation between high and low WM demand. Specifically, even in absence of main effects of diagnosis, increased PGRS was associated with decreased activation difference in the right middle-superior prefrontal cortex (BA 10/11) and the right inferior frontal gyrus (BA 45). This effect was seen in both cases and controls, and was not influenced by sex, age, or task performance. The findings support the notion of dysregulation of frontal lobe functioning as an inherited vulnerability factor in schizophrenia.

Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders

OBJECTIVE Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). METHOD A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n = 108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. RESULTS A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. CONCLUSION The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3 and the CA4 DG.

Polygenic risk score and the psychosis continuum model

Schizophrenia (SZ) and bipolar disorder (BD) are heritable, polygenic disorders with shared clinical characteristics and genetic risk indicating a psychosis continuum. This is the first study using polygenic risk score (PGRS) to investigate the localization of diagnostic subcategories along the entire psychosis spectrum.

Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case–control samples†

Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case–control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case–control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case–control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.

Up-regulation of NOTCH4 gene expression in bipolar disorder.

OBJECTIVE Immunopathogenic mechanisms have been implicated in schizophrenia and bipolar disorder, and genome-wide association studies (GWAS) point to the major histocompatibility complex, a region that contains many immune-related genes. One of the strongest candidate risk genes for schizophrenia and bipolar disorder is the NOTCH4 gene within the major histocompatibility complex. The authors investigated the NOTCH4 gene expression in individuals with bipolar disorder and schizophrenia relative to healthy comparison subjects and identified putative expression quantitative trait loci in and around the NOTCH4 gene. METHOD The authors measured and compared NOTCH4 mRNA in whole blood in 690 individuals (479 patients and 211 healthy comparison subjects) and adjusted for a range of confounders. The authors also genotyped 20 single-nucleotide polymorphisms (SNPs) and investigated possible associations between expression quantitative trait loci and NOTCH4 expression. RESULTS The authors found a strong association between NOTCH4 expression and bipolar disorder after adjusting for a range of confounders and multiple testing. In addition, seven SNPs within the NOTCH4 gene region were associated with enhanced NOTCH4 mRNA levels. Three of these expression quantitative trait loci were independent (not in linkage disequilibrium). CONCLUSIONS The results indicate that the association between NOTCH4 DNA markers and bipolar disorder is related to altered function at the mRNA level, supporting the notion that NOTCH4 pathways are involved in the pathophysiology of bipolar disorder.