Marina Mitjans

Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample

A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores—using single nucleotide polymorphism (SNP) information of SCZ GWAS—(polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample.

TPH1, MAOA, Serotonin Receptor 2A and 2C Genes in Citalopram Response: Possible Effect in Melancholic and Psychotic Depression

Background: Serotonergic genes have been widely investigated regarding antidepressant response in major depressive disorder (MDD) but results are still not univocal. Methods: 159 MDD patients treated with citalopram were genotyped and evaluated by the 21-item Hamilton Depression Rating Scale at the beginning and every 4 weeks during the 12-week follow-up. Four serotonin-related genetic variants were tested for association with treatment outcome: tryptophane hydroxylase 1 (TPH1) rs1800532, monoamine oxidase A µVNTR, serotonin 2A receptor rs6311 and serotonin 2C receptor rs6318. The effect of these polymorphisms was tested both in the whole sample and in depressive subtypes with usually higher clinical severity: psychotic and melancholic MDD. Results: No effect on response, remission and symptom improvement was found for the four polymorphisms. However, rs1800532 was found to affect the outcome depending on the MDD subtype: the A allele predicted worse response both in MDD with psychotic (F(6, 378) = 2.90; p = 0.009) and melancholic (F(6, 381) = 2.86; p = 0.0097) features. Conclusions: The A allele at TPH1 rs1800532 may be associated with citalopram efficacy only in melancholic and psychotic MDD. These results suggest the usefulness of investigating the effect of genetic variants in conjunction with specific clinical features.

Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high‐ versus low‐risk constellation regarding the accumulation model. Thereby, the brain‐expressed miR‐181 species emerged as potential “umbrella regulator”, with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.

Screening genetic variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment

RationaleThe endocannabinoid system has been implicated in the pathogenesis of major depression (MD) as well as in the mediation of antidepressant drug effects.ObjectivesTo analyze CNR1 gene variants in MD and clinical response to citalopram (selective serotonin re-uptake inhibitors [SSRI]).MethodsThe role of CNR1 gene (rs806368, rs1049353, rs806371, rs806377 and rs1535255) was investigated in 319 outpatients with MD and 150 healthy individuals. A subsample of 155 depressive patients were treated with citalopram and evaluated for response (fourth week) and remission (12th week) by the 21-item Hamilton Depression Rating Scale (HDRS).ResultsWe observed a higher frequency of rs806371 G carriers in MD patients with both presence of melancholia (p = 0.018) and psychotic symptoms (p = 0.007) than in controls. Haplotype frequency distributions between MD sample and controls showed a significant difference for Block 1 (rs806368–rs1049353–rs806371) (p = 0.008). This haplotype finding was consistent when we compared controls with MD subsample stratified by melancholia (p = 0.0009) and psychotic symptoms (p = 0.014). The TT homozygous of the rs806368 and rs806371 presented more risk of no Remission than the C carriers (p = 0.008 and 0.012, respectively). Haplotype frequency distributions according to Remission status showed a significant difference for Block 1 (p = 0.032). Also, we observed significant effect of time–sex–genotype interaction for the rs806368, showing that the C carrier men presented a better response to antidepressant treatment throughout the follow-up than TT homozygous men and women group (p = 0.026).ConclusionsThese results suggest an effect of CNR1 gene in the etiology of MD and clinical response to citalopram.

Acquisition and generalization of fear conditioning are not modulated by the BDNF-val66met polymorphism in humans.

Few studies have investigated the role of the BDNF-val66met polymorphism in fear conditioning in humans, and previous results have been inconsistent. In the present study, we examined whether the BDNF-val66met was associated with differences in the acquisition and generalization of fear during a differential conditioning paradigm in a large sample of participants (N = 141). Using three different indexes of fear learning (fear-potentiated startle, skin conductance response, and online risk ratings) no effects of the BDNF-val66met were found either on the acquisition or the generalization of conditioned fear. Taken together with previous data, our study suggests that the BDNF-val66met polymorphism has no effect on the acquisition or generalization of fear.

Genetic variability in the endocannabinoid system and 12-week clinical response to citalopram treatment: the role of the CNR1, CNR2 and FAAH genes

First line treatment of major depression is based on selective serotonin re-uptake inhibitors (SSRIs) that enhance serotonergic neurotransmission by blocking the serotonin transporter. However, clinical response is a complex phenomenon in which other systems such as the endocannabinoid system could be involved. Given the evidence for the role of the endocannabinoid system in the pathogenesis of depression as well as in the mediation of antidepressant drug effects, the aim of this study was to analyze genetic variability in the endocannabinoid system genes (CNR1, CNR2 and FAAH genes) and their role in clinical response (at week 4) and remission (at week 12) in SSRI (citalopram) treatment in a sample of 154 depressive outpatients, all of Spanish origin. All patients were treated with citalopram and followed over 12 weeks. Severity of depressive symptomatology was evaluated by means of the 21-item Hamilton Depression Rating Score (HDRS). No differences were found in any of the genotype distributions according to response or remission. The longitudinal study showed that (i) the CNR1 rs1049353-GG genotype conferred a better response to citalopram treatment in the subgroup of male patients and (ii) G allele carriers (CNR2 rs2501431) presented higher HDRS scores in the follow-up than AA homozygous allele carriers. Our results seem to suggest the involvement of CNR1 and CNR2 genes in clinical responses to citalopram treatment.

Clinical features, impulsivity, temperament and functioning and their role in suicidality in patients with bipolar disorder

Our aim was to analyse sociodemographic and clinical differences between non‐suicidal (NS) bipolar patients (BP), BP reporting only suicidal ideation (SI) and BP suicide attempters according to Columbia–Suicide Severity Rating Scale (C‐SRSS) criteria. Secondarily, we also investigated whether the C‐SRSS Intensity Scale was associated with emergence of suicidal behaviour (SB).

Exploring Genetic Variability at PI, GSK3, HPA, and Glutamatergic Pathways in Lithium Response: Association With IMPA2, INPP1, and GSK3B Genes.

Abstract Lithium is considered the first-line treatment in bipolar disorder, although response could range from an excellent response to a complete lack of response. Response to lithium is a complex phenotype in which different factors, part of them genetics, are involved. In this sense, the aim of this study was to investigate the potential association of genetic variability at genes related to phosphoinositide, glycogen synthetase kinase-3 (GSK3), hypothalamic-pituitary-adrenal, and glutamatergic pathways with lithium response. A sample of 131 bipolar patients (99 type I, 32 type II) were grouped and compared according to their level of response: excellent responders (ER), partial responders (PR), and nonresponders (NR). Genotype and allele distributions of the rs669838 (IMPA2), rs909270 (INNP1), rs11921360 (GSK3B), and rs28522620 (GRIK2) polymorphisms significantly differed between ER, PR, and NR. When we compared the ER versus PR+NR, the logistic regression showed significant association for rs669838-C (IMPA2; P = 0.021), rs909270-G (INPP1; P = 0.009), and rs11921360-A (GSK3B; P = 0.004) with lithium nonresponse. Haplotype analysis showed significant association for the haplotypes rs3791809-rs4853694-rs909270 (INPP1) and rs1732170-rs11921360-rs334558 (GSK3B) and lithium response. Our study is in line with previous studies reporting association between genetic variability at these genes and lithium response, pointing to an effect of IMPA2, INPP1, and GSK3B genes to lithium response in bipolar disorder patients. Further studies with larger samples are warranted to assess the strength of the reported associations.

Convergence of placenta biology and genetic risk for schizophrenia

Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study–derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.Early-life complications modulate the association of genomic risk and schizophrenia.

DISC1-TSNAX and DAOA genes in major depression and citalopram efficacy

BACKGROUND Major depressive disorder (MDD) is a common disease with high morbidity and still unsatisfying treatment response. Both MDD pathogenesis and antidepressant effect are supposed to be strongly affected by genetic polymorphisms. Among promising candidate genes, distrupted in schizophrenia 1 (DISC1), translin-associated factor X (TSNAX) and D-amino acid oxidase activator (DAOA) were suggested since their regulator role in neurodevelopment, neuroplasticity and neurotransmission, and previous evidence of cross-involvement in major psychiatric diseases. METHODS The present paper investigated the role of 13 SNPs within the reported genes in MDD susceptibility through a case-control (n=320 and n=150, respectively) study and in citalopram efficacy (n=157). Measures of citalopram efficacy were response (4th week) and remission (12th week). Pharmacogenetic findings were tested in the STAR(⁎)D genome-wide dataset (n=1892) for replication. RESULTS Evidence of association among rs3738401 (DISC1), rs1615409 and rs766288 (TSNAX) and MDD was found (p=0.004, p=0.0019, and p=0.008, respectively). A trend of association between remission and DISC1 rs821616 and DAOA rs778294 was detected, and confirmation was found for rs778294 by repeated-measure ANOVA (p=0.0008). In the STAR(⁎)D a cluster of SNPs from 20 to 40Kbp from DISC1 findings in the original sample was associated with citalopram response, as well as rs778330 (12,325bp from rs778294). LIMITATIONS Relatively small size of the original sample and focus on only three candidate genes. CONCLUSIONS The present study supported a role of DISC1-TSNAX variants in MDD susceptibility. On the other hand, genetic regions around DAOA rs778294 and DISC1 rs6675281-rs1000731 may influence citalopram efficacy.