Schizophrenia is a severe and multifactorial disorder with an unknown causative pathophysiology. Abnormalities in neurodevelopmental and aging processes have been reported. Relative telomere length (RTL) and DNA methylation age (DMA), well-known biomarkers for estimating biological age, are both commonly altered in patients with schizophrenia compared to healthy controls. However, few studies investigated these aging biomarkers in first-episode psychosis (FEP) and in antipsychotic-naïve patients. To cover the existing gap regarding DMA and RTL in FEP and antipsychotic treatment, we aimed to verify whether those aging markers could be associated with psychosis and treatment response. Thus, we evaluated these measures in the blood of FEP antipsychotic-naïve patients and healthy controls (HC), as well as the response to antipsychotics after 10 weeks of treatment with risperidone. RTL was measured in 392 subjects, being 80 FEP and 312 HC using qPCR, while DMA was analyzed in a subset of 60 HC, 60 FEP patients (antipsychotic-naïve) and 59 FEP-10W (after treatment) using the “Multi-tissue Predictor”and the Infinium HumanMethylation450 BeadChip Kit. We observed diminished DMA and longer RTL in FEP patients before treatment compared to healthy controls, indicating a decelerated aging process in those patients. We found no statistical difference between responder and non-responder patients at baseline for both markers. An increased DMA was observed in patients after 10 weeks of treatment, however, after adjusting for blood cell composition, no significant association remained. Our findings indicate a decelerated aging process in the early phases of the disease.

Age-related alteration in neural stem cell function is linked to neurodegenerative conditions and cognitive decline. In rodents, this can be reversed by exposure to a young systemic milieu and conversely, the old milieu can inhibit stem cell function in young rodents. In this study, we investigated the in vitro effect of the human systemic milieu on human hippocampal progenitor cells (HPCs) using human serum from early adulthood, mid-life and older age. We showed that neuroblast number following serum treatment is predictive of larger dentate gyrus, CA3, CA4 and whole hippocampus volumes and that allogeneic human serum from asymptomatic older individuals induced a two-fold increase in apoptotic cell death of HPCs compared with serum from young adults. General linear models revealed that variability in markers of proliferation and differentiation was partly attributable to use of antihypertensive medication and very mild cognitive decline among older subjects. Finally, using an endophenotype approach and whole-genome expression arrays, we showed upregulation of established and novel ageing molecular hallmarks in response to old serum. Serum from older subjects induced a wide range of cellular and molecular phenotypes, likely reflecting a lifetime of environmental exposures. Our findings support a role for the systemic enviroment in neural stem cell maintenance and are in line with others highlighting a distinction between neurobiological and chronological ageing. Finally, the herein described serum assay can be used by future studies to further analyse the effect of environmental exposures as well as to determine the role of the systemic environment in health and disease.

We performed a transcriptome-wide meta-analysis and gene co-expression network analysis to identify genes and gene networks dysregulated in the peripheral blood of bipolar disorder (BD) cases relative to unaffected comparison subjects, and determined the specificity of the transcriptomic signatures of BD and schizophrenia (SZ). Nineteen genes and 4 gene modules were significantly differentially expressed in BD cases. Thirteen gene modules were shown to be differentially expressed in a combined case-group of BD and SZ subjects called "major psychosis", including genes biologically linked to apoptosis, reactive oxygen, chromatin remodeling, and immune signaling. No modules were differentially expressed between BD and SZ cases. Machine-learning classifiers trained to separate diagnostic classes based solely on gene expression profiles could distinguish BD cases from unaffected comparison subjects with an area under the curve (AUC) of 0.724, as well as BD cases from SZ cases with AUC = 0.677 in withheld test samples. We introduced a novel and straightforward method called "polytranscript risk scoring" that could distinguish BD cases from unaffected subjects (AUC = 0.672) and SZ cases (AUC = 0.607) significantly better than expected by chance. Taken together, our results highlighted gene expression alterations common to BD and SZ that involve biological processes of inflammation, oxidative stress, apoptosis, and chromatin regulation, and highlight disorder-specific changes in gene expression that discriminate the major psychoses.

Clozapine is an important antipsychotic drug. However, its use is often accompanied by metabolic adverse effects and, in rare instances, agranulocytosis. The molecular mechanisms underlying these adverse events are unclear. To gain more insights into the response to clozapine at the molecular level, we exposed lymphoblastoid cell lines (LCLs) to increasing concentrations of clozapine and measured genome-wide gene expression and DNA methylation profiles. We observed robust and significant changes in gene expression levels due to clozapine (n = 463 genes at FDR < 0.05) affecting cholesterol and cell cycle pathways. At the level of DNA methylation, we find significant changes upstream of the LDL receptor, in addition to global enrichments of regulatory, immune and developmental pathways. By integrating these data with human tissue gene expression levels obtained from the Genotype-Tissue Expression project (GTEx), we identified specific tissues, including liver and several tissues involved in immune, endocrine and metabolic functions, that clozapine treatment may disproportionately affect. Notably, differentially expressed genes were not enriched for genome-wide disease risk of schizophrenia or for known psychotropic drug targets. However, we did observe a nominally significant association of genetic signals related to total cholesterol and low-density lipoprotein levels. Together, these results shed light on the biological mechanisms through which clozapine functions. The observed associations with cholesterol pathways, its genetic architecture and specific tissue effects may be indicative of the metabolic adverse effects observed in clozapine users. LCLs may thus serve as a useful tool to study these molecular mechanisms further.### Competing Interest StatementThe authors have declared no competing interest.

Cannabis can induce acute psychotic symptoms in healthy individuals and exacerbate pre-existing psychotic symptoms in patients with schizophrenia. Inappropriate salience allocation is hypothesised to be central to the association between dopamine dysregulation and psychotic symptoms. This study examined whether cannabis use is associated with self-reported salience dysfunction and schizotypal symptoms in a non-clinical population. 910 University students completed the following questionnaire battery: the cannabis experience questionnaire modified version (CEQmv); schizotypal personality questionnaire (SPQ); community assessment of psychic experience (CAPE); aberrant salience inventory (ASI). Mediation analysis was used to test whether aberrant salience mediated the relationship between cannabis use and schizotypal traits. Both frequent cannabis consumption during the previous year and ASI score predicted variation across selected positive and disorganised SPQ subscales. However, for the SPQ subscales ‘ideas of reference’ and ‘odd beliefs’, mediation analysis revealed that with the addition of ASI score as a mediating variable, current cannabis use no longer predicted scores on these subscales. Similarly, cannabis use frequency predicted higher total SPQ as well as specific Positive and Disorganised subscale scores, but ASI score as a mediating variable removed the significant predictive relationship between frequent cannabis use and ‘odd beliefs’, ‘ideas of reference’, ‘unusual perceptual experiences’, ‘odd speech’, and total SPQ scores. In summary, cannabis use was associated with increased psychometric schizotypy and aberrant salience. Using self-report measures in a non-clinical population, the cannabis-related increase in selected positive and disorganised SPQ subscale scores was shown to be, at least in part, mediated by disturbance in salience processing mechanisms.

Schizophrenia (SCZ) is a severe mental disorder affecting ~1% of the population and is characterized by the presence of psychosis and other features, such as negative (i.e., flattened affect and social withdrawal) and disorganization symptoms (e. g. impaired cognitive function, disorganized speech and behavior). Symptomatic and psychosocial deterioration progress rapidly during the period just after the onset of the disorder, termed the First Episode of Schizophrenia (FES). In this study, we aimed to test if the SCZ Polygenic Risk Score (PRS) was associated with clinical symptoms at the FES, nine weeks after initiation of risperidone treatment (FES-9W) and with the response to risperidone. We performed a detailed clinical assessment of 60 antipsychotic naïve patients in their FES and, again, after nine weeks of standardized treatment with Risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson Regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered as significant a p-value<0.05/36 (Bonferroni correction for multiple comparisons). The polygenic risk score was significantly different between cases and controls with a best p-threshold of 0.0112 (NSNPs=21,622) and an explained variance of 0.19 (Naegelkerk's pseudo-r2). Within-cases, we found a positive association of the best PRS score with the PANSS excitement factor (five-factor model) (p-value=0.0003). The PRS was slightly positively correlated with depressive symptoms at baseline (CDSS total, p-value=0.003) but was negatively associated with depressive symptoms after risperidone treatment (CDSS total, p-value=0.001). Looking at response to risperidone, we observed a positive association for ΔCDSS (p-value=0.0006). However, there was no correlation between Δtotal PANSS and PRS. We verified that the schizophrenia PRS was also able to distinguish cases from control in this south-eastern Brazilian sample, with a similar variance explained (~0.19, observed scale) to that seen in Northern European populations. One strength of our study is that all patients were antipsychotic-naïve at the baseline and received the same antipsycotic treatment for relatively the same time. It is well known that some patients may have an increase of depressive symptoms once the positive symptoms remit, however, there is no study so far that evaluated the relation between PRS and post-schizophrenia depression. Taken together, these results suggest that FES patients who present with higher depressive and excitement symptoms and who show reduction in these dimensions after treatment with risperidone have a significantly higher genetic risk for SCZ (as measured by PRS). These results highlight the importance of studying schizophrenia, and other disorders, in the early stages to understand the relationship between polygenic genetic risk and phenotypic features.

The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences. We investigated 12 genes in 394 individuals (27 individuals with CHR, 70 antipsychotic-naive individuals with FEP, 157 CSZ patients, and 140 healthy controls (HCs)). For a subsample, genotype data were also available, and we extracted SNPs that were previously associated with the expression of selected genes in whole blood or brain tissue. We generated a mediation model in which a putative cause (SNP) is related to a presumed effect (disorder) via an intermediate variable (gene expression). MBP and NDEL1 were upregulated in FEP compared to all other groups; DGCR8 was downregulated in FEP compared to HC and CHR; DGCR2 was downregulated in CSZ compared to FEP and HCs; DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression; and UFD1 was upregulated in CSZ and CHR compared to FEP and HC. Our results indicated changes in gene expression profiles throughout the different clinical stages of SZ, reinforcing the need for staging approaches to better capture SZ heterogeneity.

The active form of vitamin B6, pyridoxal phosphate (PLP), is essential for human metabolism. The brain is dependent on vitamin B6 for its neurotransmitter balance. To obtain insight into the genetic determinants of vitamin B6 homeostasis, we conducted a genome-wide association study (GWAS) of the B6 vitamers pyridoxal (PL), PLP and the degradation product of vitamin B6, pyridoxic acid (PA). We collected a unique sample set of cerebrospinal fluid (CSF) and plasma from the same healthy human subjects of Dutch ancestry (n = 493) and included concentrations and ratios in and between these body fluids in our analysis. Based on a multivariate joint analysis of all B6 vitamers and their ratios, we identified a genome-wide significant association at a locus on chromosome 1 containing the ALPL (alkaline phosphatase) gene (minimal p = 7.89 × 10-10, rs1106357, minor allele frequency (MAF) = 0.46), previously associated with vitamin B6 levels in blood. Subjects homozygous for the minor allele showed a 1.4-times-higher ratio between PLP and PL in plasma, and even a 1.6-times-higher ratio between PLP and PL in CSF than subjects homozygous for the major allele. In addition, we observed a suggestive association with the CSF:plasma ratio of PLP on chromosome 15 (minimal p = 7.93 × 10-7, and MAF = 0.06 for rs28789220). Even though this finding is not reaching genome-wide significance, it highlights the potential of our experimental setup for studying transport and metabolism across the blood⁻CSF barrier. This GWAS of B6 vitamers identifies alkaline phosphatase as a key regulator in human vitamin B6 metabolism in CSF as well as plasma. Furthermore, our results demonstrate the potential of genetic studies of metabolites in plasma and CSF to elucidate biological aspects underlying metabolite generation, transport and degradation.

Background The study of the early stages of schizophrenia, the First-Episode Psychosis (FEP), is critical given that brain abnormalities and cognitive deficits are already present. Although less investigated than chronic schizophrenia, FEP individuals have a shorter period of medication and duration of symptoms. In this study, we aimed to identify genetic markers, using whole DNA methylation, for psychotic disorder and antipsychotic treatment in blood of a FEP cohort before and after two months of risperidone. Methods Sixty controls and sixty antipsychotic naïve FEP patients followed-up for two months after risperidone (FEP-2M) were recruited. All patients were 16–40 years old and have met the criteria of psychotic diagnoses according to DSM-IV. We generated the DNA methylation data using the Human Illumina 450K BeadChip microarray. We used limma R package, using two separate analyses: FEP x HC and FEPxFEP-2M (paired); and addind sex, age, smoking data and cell type proportion as covariates. We considered as significant Differentially Methylated Positions (DMPs) with p value lower than 0.05 after a Bonferroni correction for multiple comparisons and differentially methylated regions (DMRs) with at least two significant DMPs (FDR) within a 500bp region. Results We found 5 DMRs and 16 DMPs comparing controls and FEP, and 14 DMRs and 77 DMPs between FEP before and after treatment. Discussion To our knowledge, this is the first study to find DMRs in a longitudinal cohort of antipsychotic naïve FEP patients. Collectively, DMRs in the longitudinal comparison seem to be related to the adverse effects and the response to risperidone. Notably, the most associated genomic region in schizophrenia (previously reported by the PGC), the MHC region, is differentially methylated in patients after the treatment, demonstrating an epigenetic modification caused by risperidone in an important schizophrenia genomic region. Identifying the genetic and molecular changes of drug response is one of the first steps through personalized medicine, further studies should replicate these results and aim antipsychotic naive individuals treated with other antipsychotics.

BackgroundMajor depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings.MethodsIn this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions.ResultsPatients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5.ConclusionsThe increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.

Purpose: Inflammation in an osteoarthritic joint predominantly causes pain and stimulates cartilage matrix breakdown. Triamcinolone acetonide (TAA) is injected intra-articularly to alleviate pain and temporarily reduce inflammation. Since repeat bolus steroid injections entail risks, local sustained TAA release can overcome such disadvantages. PLGA formulations of TAA has been shown to effectively prolong pain inhibition in OA but is limited to 12 weeks. A novel polyesteramide (PEA) microsphere platform based on natural α-amino acids previously showed release in the joint for over 3 months and release in vitro for more than 12 months. To evaluate its capacity for sustained inhibition of pain and inflammation, PEA microspheres loaded with TAA (PEA/TAA) were locally delivered in an adapted rat model of acute inflammatory arthritis and compared to PLGA (PLGA/TAA) Methods: Localized synovitis was induced in the left knee of 18 adult Sprague-Dawley rats by intra-articular injection of streptococcal-cell-wall-peptidoglycan-polysaccharide (PGPS with 5 mg rhamnose/mL) (priming, day -28). Rats were divided in 3 groups with n=6. Control group, injection of PEA/TAA and injection of PLGA/TAA delivery system. Synovitis flare-ups were reactivated on day 0, 28 and 56 by administration of intravenous PGPS. 2.5 hours prior first reactivation (day 0), 25 μl unloaded and loaded microspheres with 2.5 mg/ml TAA, using PEA and PLGA polymer as carrier (2.5 mg TAA/ml) were intra-articularly delivered in the affected knee. Joint thickness and signs of pain-like behavior such as lameness and referred mechanical hypersensitivity were measured every 0, 1, 2, 4, 15 and 21st day. Dynamic weight bearing was measured on day 0, 2 and 15 after PGPS administration and served as non-evoked pain-like behavior. Rats were terminated after 12 weeks, scanned with μCT and knees histologically analyzed. Macroscopic and microscopic analysis of Spleen and liver served as identification method of potential systemic side effects. Observer of read outs was blinded at day of injection. Results: The control group showed that the modified animal model was able to function as a suitable pain model related to arthritis. An increase of joint swelling in the affected knee and minor swelling in the contralateral knee was observed. Reactivation of inflammation was performed via the tail vein of the animal and therefore systemic effects established Regardless this phenomena, a difference in joint swelling and synovitis of treated and untreated collateral knee was observed but without statistical significance. For PLGA and PEA releasing particles, the effect after the first reactivation at day 0 days is similar as the inflammation was effectively suppressed. PEA platform continued with this behavior for the upcoming two activations at day 28 and 56 whereas PLGA platform could not prevent the flare up of the inflammation. The priming with PGPS showed that the swelling is retrogressive back to the baseline within the 28 days before the reactivation, even without treatment with TAA. PEA/TAA suppresses the swelling and related inflammation for all three reactivations which might be an indication for the retention of TAA. This result is strengthened by the fact that PLGA/TAA doesn’t show this behavior at the second reactivation or third reactivation but can be rather compared to the control group which was not treated. After a period of 12 weeks the osteophyte and bone cyst formation were identified in the knees treated with PLGA/TAA but not in PEA/TAA treated joints. Conclusions: Sustained suppression of synovitis by controlled TAA release from the PEA platform provides prolonged reduction of joint inflammation, functional improvement and pain relief over an extended period after single injection. In addition, an improvement of PEA platform over PLGA MPs was observed with respect to joint thickness, osteophyte and bone cyst formation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

ABSTRACT Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P<1×10 -4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters ( CACNA1C , GRIN2A , SCN2A , SLC4A1 ), synaptic components ( RIMS1 , ANK3 ), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~ 73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~ 17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face-related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing.

Antioxidants and telomere length are potential biomarkers for individuals’ exposure and ability to cope with environmental stressors. However, intraspecific variations in antioxidant alterations due to natural, life cycle related stress, have been rarely estimated. We investigated those changes in wild-derived house mice in a longitudinal study with natural sibling competition as a stressor. Blood was used for telomere length measurements at 8-weeks age and for several selected antioxidants at 8-weeks and 6-months age. Our results show that most of the antioxidants increase during that time, indicating that antioxidant-system continues to develop after early development and sexual maturation. In addition females had higher antioxidant-levels than males. Mice with longer telomeres had also higher superoxide dismutase-activity and more glutathione than mice with shorter telomeres, meaning that long telomeres are associated with better antioxidant defense at maturation and during later life. Sibling competition at early age affected superoxide dismutase-levels at 6-months, but only in females. Females, which were lighter than the average of the litter had low superoxide dismutase –activity in later adulthood, indicating delayed negative effect of sibling competition on antioxidant defense. Our results highlight that sex and developmental stage are crucial in intraspecific comparisons of the antioxidant status and its alterations.

The exposure to biological abnormalities proper of the psychiatric conditions (e.g. inflammation, oxidative stress, poor sleep and nutrition, insufficient exercise, cigarette smoking) may lead to accelerated cellular aging. Telomere length has been used as an index of biological aging in psychiatric illnesses and, using the same rationale, a novel age acceleration predictor is emerging: DNA Methylation Age (DMA). We tested the hypothesis that DMA could be associated with Schizophrenia (SCZ), its psychopathology and response to treatment in early stages of illness. We assayed 60 antipsychotic-naïve First Episode of Psychosis patients (FEP), the same individuals after 2-month risperidone-exclusive treatment and 59 Healthy Controls (HC), totaling 119 participants. Psychiatric diagnosis was assessed using the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I). We used the Positive And Negative Syndrome Scale (PANSS) to assess positive and negative symptoms and general psychopathology. We considered as risperidone-responders those with a decrease of at least 30% in PANSS. Telomere length was determined using a multiplex qPCR assay, whereas DNA methylation age was estimated by methylation levels at 353 genomic sites (Horvath, 2013) from Illumina 450 K methylation microarray. We found a correlation between chronological age and DMA (r2=0.899; p<0.001), but we found no correlation between TL and chronological age or TL and DMA. In patients, DMA was not correlated to total, negative, positive, and general psychopathology PANSS. On the other hand, our data demonstrate significant statistical difference between HC and antipsychotic-naïve FEP, with patients having a nominally lower baseline DMA mean than HC (t=2.260; df=117, p=0.026), including after adjustment for chronological age. After risperidone treatment, no differences in DMA remained comparing HC and FEP. Moreover, there was no difference in DMA between responders and non-responders to risperidone. Logistic regression modelling showed that DMA (with age as a co-variable) is nominally associated with case status (FEP and HC) (p<0.022; df=1). Our data shows that the DMA is highly correlated to chronological age but not to TL, suggesting DMA could be a better aging measure than TL. In addition, we showed that DMA does not associate with either symptoms or psychopathology, but may be associated with increased risk for schizophrenia in treatment naïve patients.

The relation of heavy cannabis use with decreased neuropsychological function has frequently been described but the underlying biological mechanisms are still largely unknown. This study investigates the relation of cannabis use with genome wide gene expression and subsequently examines the relations with neuropsychological function. Genome-wide gene expression in whole blood was compared between heavy cannabis users (N = 90) and cannabis naive participants (N = 100) that were matched for psychotic like experiences. The results were validated using quantitative real-time PCR. Psychotic like experiences were assessed using the Compre-hensive Assessment of Psychotic Experiences (CAPE). Neuropsychological function was esti-mated using four subtasks of the Wechsler Adult Intelligence Scale (WAIS). Subsequent in vitro studies in monocytes and a neuroblastoma cell line investigated expression changes in response to two major psychotropic components of cannabis; tetrahydrocannabinol (THC) and cannabid-iol (CBD). mRNA expression of Protein Tyrosine Phosphatase Receptor Type F PolypeptideInteracting- Protein Alpha-2 (PPFIA2) was significantly higher in cannabis users (LogFold Change 0.17) and confirmed by qPCR analysis. PPFIA2 expression level was negatively correlated with estimated intelligence (B = -22.9, p = 0.002) also in the 100 non-users (B = -28.5, p = 0.037). In vitro exposure of monocytes to CBD led to significant increase in PPFIA2 expression. However, exposure of monocytes to THC and neuroblastoma cells to THC or CBD did not change PPFIA2 expression. Change in PPFIA2 gene expression in response to cannabinoids is a putative mech-anism by which cannabis could influence neuropsychological functions. The findings warrant further exploration of the role of PPFIA2 in cannabis induced changes of neuropsychological function, particularly in relation to CBD. (c) 2019 Published by Elsevier B.V.

Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10−5). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10−18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p < 0.05). Lithium may therefore confer its anti-ageing effects by moderating the expression of genes responsible for normal telomere length regulation. This is supported by our bipolar disorder sample, which shows that polygenic risk scores explain a higher proportion of the variance in telomere length amongst chronic lifetime lithium users (variance explained = 8.9%, p = 0.01), compared to non-users (p > 0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual’s inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium’s anti-ageing efficacy.

Most literature to-date suggests that shortened telomere length (TL) amongst psychiatric disorder patients represents an effect of having the disease or the stresses precipitating it due to an increased release of stress hormones, immuno-inflammatory activation or oxidative stress. However, recent research indicates that a genetic predisposition to shortened TL might actually act as a risk factor for some types of mood disorders, and therefore shortened TL may play a causative role.TL has been associated with brain morphology, in the hippocampus, amygdala, posterior cingulate and precuneus. So far, no previous studies have considered the role TL may have on brain function during tasks relevant to mood disorders.

Psychiatric illnesses are complex and polygenic. They are associated with widespread alterations in the brain, which are partly influenced by genetic factors. There have been some attempts to relate polygenic risk scores (PRS) - a measure of the overall genetic risk an individual carries for a disorder - to brain structure using univariate methods. However, PRS are likely associated with distributed and covarying effects across the brain. We therefore used multivariate machine learning in this proof-of-principle study to investigate associations between brain structure and PRS for four psychiatric disorders; attention deficit-hyperactivity disorder (ADHD), autism, bipolar disorder and schizophrenia. The sample included 213 individuals comprising patients with depression (69), bipolar disorder (33), and healthy controls (111). The five psychiatric PRSs were calculated based on summary data from the Psychiatric Genomics Consortium. T1-weighted magnetic resonance images were obtained and voxel-based morphometry was implemented in SPM12. Multivariate relevance vector regression was implemented in the Pattern Recognition for Neuroimaging Toolbox (PRoNTo). Across the whole sample, a multivariate pattern of grey matter significantly predicted the PRS for autism (r = 0.20, pFDR = 0.03; MSE = 4.20 x 10(-5), pFDR = 0.02). For the schizophrenia PRS, the MSE was significant (MSE = 1.30 x 10(-5), pFDR = 0.02) although the correlation was not (r = 0.15, p(FDR) = 0.06). These results lend support to the hypothesis that polygenic liability for autism and schizophrenia is associated with widespread changes in grey matter concentrations. These associations were seen in individuals not affected by these disorders, indicating that this is not driven by the expression of the disease, but by the genetic risk captured by the PRSs.