Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19.

In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12-1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80-0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86-0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.

Differences in the gut microbiome of young adults with schizophrenia spectrum disorder: using machine learning to distinguish cases from controls.

While an association between the gut microbiome and schizophrenia spectrum disorders (SSD) has been suggested, the existing evidence is still inconclusive. To this end, we analyzed bacteria and bacterial genes in feces from 52 young adult SSD patients and 52 controls using fecal shotgun metagenomic sequencing. Compared to controls, young SSD patients were found to have significantly lower α-diversity and different ß-diversity both regarding bacterial species (i.e., taxonomic diversity) and bacterial genes (i.e., functional diversity). Furthermore, the α-diversity measures 'Pielou's evenness' and 'Shannon' were significantly higher for both bacterial species, bacterial genes encoding enzymes and gut brain modules in young SSD patients on antipsychotic treatment (young SSD not on antipsychotics=9 patients, young SSD on antipsychotics=43 patients). We also applied machine learning classifiers to distinguish between young SSD patients and healthy controls based on their gut microbiome. Results showed that taxonomic and functional data classified young SSD individuals with an accuracy of ≥ 70% and with an area under the receiver operating characteristic curve (AUROC) of ≥ 0.75. Differential abundance analysis on the most important features in the classifier models revealed that most of the species with higher abundance in young SSD patients had their natural habitat in the oral cavity. In addition, many of the modules with higher abundance in young SSD patients were amino acid biosynthesis modules. Moreover, the abundances of gut-brain modules of butyrate synthesis and acetate degradation were lower in the SSD patients compared to controls. Collectively, our findings continue to support the presence of gut microbiome alterations in SSD and provide support for the use of machine learning algorithms to distinguish patients from controls based on gut microbiome profiles.

Bacterial gut microbiome differences in adults with ADHD and in children with ADHD on psychostimulant medication.

Recent evidence suggests that there is a link between neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD), and the gut microbiome. However, most studies to date have had low sample sizes, have not investigated the impact of psychostimulant medication, and have not adjusted for potential confounders, including body mass index, stool consistency and diet. To this end, we conducted the largest, to our knowledge, fecal shotgun metagenomic sequencing study in ADHD, with 147 well-characterized adult and child patients. For a subset of individuals, plasma levels of inflammatory markers and short-chain fatty acids were also measured. In adult ADHD patients (n = 84), compared to controls (n = 52), we found a significant difference in beta diversity both regarding bacterial strains (taxonomic) and bacterial genes (functional). In children with ADHD (n = 63), we found that those on psychostimulant medication (n = 33 on medication vs. n = 30 not on medication) had (i) significantly different taxonomic beta diversity, (ii) lower functional and taxonomic evenness, (iii) lower abundance of the strain Bacteroides stercoris CL09T03C01 and bacterial genes encoding an enzyme in vitamin B12 synthesis, and (iv) higher plasma levels of vascular inflammatory markers sICAM-1 and sVCAM-1. Our study continues to support a role for the gut microbiome in neurodevelopmental disorders and provides additional insights into the effects of psychostimulant medication. However, additional studies are needed to replicate these findings and examine causal relationships with the disorder.

Lithium and risk of cardiovascular disease, dementia and venous thromboembolism.

OBJECTIVE: To determine if long-term lithium treatment is associated with protective effects or increased risk of vascular, neurological, and renal disorders. METHODS: Using nationwide registers, we included all citizens of Finland with dispensations of lithium for three or more consecutive years between 1995 and 2016. We identified 9698 cases and matched 96,507 controls without lithium treatment. Studied outcomes were vascular, neurological, renal disorders, and suicide. Analyses were performed applying Cox proportional hazards modeling in full cohort and in further subcohort analysis of individuals with a comparable diagnosis of mood or psychotic disorder. RESULTS: Lithium users had a significantly higher overall disease burden compared to matched population controls, including a higher risk of cardiovascular and cerebrovascular disorders and dementia. However, compared to individuals with a diagnosis of mood or psychotic disorders without lithium treatment, we observed a lower risk of cardiovascular and cerebrovascular disorders (HR = 0.80, 99% CI = 0.73-0.89), and no significant difference for dementia (HR = 1.15, 99% CI = 0.99-1.33), in lithium users. Pulmonary embolism was more common in the lithium-treated cases both in comparison to the general population (HR = 2.86, 99% CI = 2.42-3.37) and in comparison to the psychiatric subcohort (HR = 1.68, 99% CI = 1.31-2.17). Similarly, the risks of Parkinson's disease and kidney disease were higher in both comparisons. CONCLUSIONS: We conclude that individuals prescribed lithium have a lower risk of cardiovascular and cerebrovascular disease, but no marked effect on dementia, compared to individuals with a mood or psychotic disorder not prescribed lithium. Venous thromboembolism, Parkinson's disease, and kidney disease were significantly more prevalent in individuals prescribed lithium.

Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial.

BACKGROUND: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. METHODS: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18-40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. RESULTS: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. CONCLUSIONS: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. TRIAL REGISTRATION: This study is based on a study registered at ClinicalTrials.gov, NCT03392701 . Registered 21 December 2017.

Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders.

The improvement of experimental models for disorders requires a constant approximation towards the dysregulated tissue. In psychiatry, where an impairment of neuronal structure and function is assumed to play a major role in disease mechanisms and symptom development, this approximation is an ongoing process implicating various fields. These include genetic, animal, and post-mortem studies. To test hypotheses generated through these studies, in vitro models using non-neuronal cells such as fibroblasts and lymphocytes have been developed. For brain network disorders, cells with neuronal signatures would, however, represent a more adequate tissue. Considering the limited accessibility of brain tissue, research has thus turned towards neurons generated from induced pluripotent stem cells as well as directly induced neurons, cerebral organoids, and olfactory neuroepithelium. Regarding the increasing importance and amount of research using these neuronal cells, this review aims to provide an overview of all these models to make sense of the current literature. The development of each model system and its use as a model for the various psychiatric disorder categories will be laid out. Also, advantages and limitations of each model will be discussed, including a reflection on implications and future perspectives.

Enteric short-chain fatty acids promote proliferation of human neural progenitor cells.

Short-chain fatty acids (SCFAs) are a group of fatty acids predominantly produced during the fermentation of dietary fibers by the gut anaerobic microbiota. SCFAs affect many host processes in health and disease. SCFAs play an important role in the 'gut-brain axis', regulating central nervous system processes, for example, cell-cell interaction, neurotransmitter synthesis and release, microglia activation, mitochondrial function, and gene expression. SCFAs also promote the growth of neurospheres from human neural stem cells and the differentiation of embryonic stem cells into neural cells. It is plausible that maternally derived SCFAs may pass the placenta and expose the fetus at key developmental periods. However, it is unclear how SCFA exposure at physiological levels influence the early-stage neural cells. In this study, we explored the effect of SCFAs on the growth rate of human neural progenitor cells (hNPCs), generated from human embryonic stem cell line (HS980), with IncuCyte live-cell analysis system and immunofluorescence. We found that physiologically relevant levels (µM) of SCFAs (acetate, propionate, butyrate) increased the growth rate of hNPCs significantly and induced more cells to undergo mitosis, while high levels (mM) of SCFAs had toxic effects on hNPCs. Moreover, no effect on apoptosis was observed in physiological-dose SCFA treatments. In support, data from q-RT PCR showed that SCFA treatments influenced the expression of the neurogenesis, proliferation, and apoptosis-related genes ATR, BCL2, BID, CASP8, CDK2, E2F1, FAS, NDN, and VEGFA. To conclude, our results propose that SCFAs regulates early neural system development. This might be relevant for a putative 'maternal gut-fetal brain-axis'. Cover Image for this issue: doi: 10.1111/jnc.14761.

Aberrant inflammatory profile in acute but not recovered anorexia nervosa.

Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and relapse rates. Even though changes in inflammatory markers and cytokines are known to accompany cachexia associated with somatic disorders such as cancer and chronic kidney disorder, studies on inflammatory markers in AN are rare and typically include few individuals. Here, we utilize an Olink Proteomics inflammatory panel to explore the concentrations of 92 preselected inflammation-related proteins in plasma samples from women with active AN (N = 113), recovered from AN (AN-REC, N = 113), and normal weight healthy controls (N = 114). After correction for multiple testing, twenty-five proteins differed significantly between the AN group and controls (lower levels: ADA, CCL19, CD40, CD5, CD8A, CSF1, CXCL1, CXCL5, HGF, IL10RB, IL12B, 1L18R1, LAP TGFß1, MCP3, OSM, TGFα, TNFRSF9, TNFS14 and TRANCE; higher levels: CCL11, CCL25, CST5, DNER, LIFR and OPG). Although more than half of these differences (N = 15) were present in the comparison between AN and AN-REC, no significant differences were seen between AN-REC and controls. Furthermore, twenty-five proteins correlated positively with BMI (ADA, AXIN1, CASP8, CD5, CD40, CSF1, CXCL1, CXCL5, EN-RAGE, HGF, IL6, IL10RB, IL12B, IL18, IL18R1, LAP TGFß1, OSM, SIRT2, STAMBP, TGFα, TNFRSF9, TNFS14, TRANCE, TRAIL and VEGFA) and four proteins correlated negatively with BMI (CCL11, CCL25, CCL28 and DNER). These results suggest that a dysregulated inflammatory status is associated with AN, but, importantly, seem to be confined to the acute illness state.

Association of Catechol-O-methyltransferase (COMT Val158Met) with future risk of cardiovascular disease in depressed individuals - a Swedish population-based cohort study.

BACKGROUND: Catechol-O-methyltransferase (COMT Val158Met) has been implicated in both depression and cardiovascular disease. The purpose of this study was to assess if COMT Val158Met, which influences the COMT enzyme activity, has an effect on the risk of cardiovascular disease (CVD) in individuals with a history of depression and also to determine if the risk differs depending on gender. METHODS: Data from a longitudinal cohort study of mental health among Swedish adults was used. Depression was assessed twice 3 years apart for each participant, in 1998-2001 and 2001-2003. Saliva DNA was contributed by 4349 (41.7%) of the participants and 3525 was successfully genotyped for COMT Val158Met. Participants were followed up until December 2014 from the National Patient register with regard to cardiovascular outcomes (hypertensive or ischemic heart disease, and stroke). RESULTS: Those with depression and the high COMT enzyme activity genotype (Val/Val) had almost a three-fold increased risk of later CVD (OR 3.6; 95% CI: 2.0-6.6) compared to those non-depressed carrying the Val/Val allele. This effect on risk for CVD was higher in women compared to men (OR 7.0; 95% CI: 3.0-14.0 versus OR 2.1; 95% CI: 1.0-6.8). Both additive interaction (attributable proportion (AP) = 0.56; 95% CI: 0.24-0.90 and synergy index (SI) = 4.39; 1.0-18.7) and multiplicative interaction (log likelihood test p = 0.1) was present between depression and COMT Val158Met in predicting risk of later CVD. CONCLUSION: High COMT activity genotype Val158Met increased the risk of CVD in depressed persons. The risk was higher in women compared to men.

Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice.

Diet-related health issues such as nonalcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet-induced changes (e.g., hyperlipidemia) and the ensuing inflammation have remained elusive so far. We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of low-density lipoprotein receptor-deficient mice on a Western-type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that malondialdehyde (MDA) epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo. MDA-induced cytokine secretion in vitro was dependent on the presence of the scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in low-density lipoprotein receptor-deficient mice on a Western-type diet. CONCLUSION: Accumulation of MDA epitopes plays a major role during diet-induced hepatic inflammation and can be ameliorated by administration of an anti-MDA antibody. (Hepatology 2017;65:1181-1195).

Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies.

Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monocytes to produce interleukin 8, which can be inhibited by a monoclonal IgM with specificity for MDA epitopes. Finally, we show that MDA(+) MPs are elevated at the culprit lesion site of patients with STE-MI. Our results identify a subset of OSE(+) MPs that are bound by OxLDL-specific IgM. These findings demonstrate a novel mechanism by which anti-OxLDL IgM antibodies could mediate protective functions in CVD.

Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD-A Randomized Controlled Trial.

Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota-gut-brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1ß-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels.

Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden.

BACKGROUND: Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. METHODS: We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipoläR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipoläR, and the Swedish prescription registry. The median time between timepoints was 1·07 years for cohort 1 and 1·09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. FINDINGS: 2357 patients who were administered lithium (1423 women [60·4%] and 934 men [39·6%]; mean age 53·6 years [range 17-89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R2]: R2cohort1=0·41 and R2cohort2=0·31; both p<0·0001), sex (R2cohort1=0·0063 [p=0·045] and R2cohort2=0·026 [p<0·0001]), eGFR (R2cohort1=0·38 and R2cohort2=0·20; both p<0·0001), comedication with diuretics (R2cohort1=0·0058 [p=0·014] and R2cohort2=0·0026 [p<0·0001]), and agents acting on the renin-aldosterone-angiotensin system (R2cohort1=0·028 and R2cohort2=0·015; both p<0·0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R2cohort1=0·13 and R2cohort2=0·15; both p<0·0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; ß=-0·053 [95% CI -0·071 to -0·034]; p<0·00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0·0014, corrected FDR=0·04) and cortex of the kidney (p=0·0015, corrected FDR=0·04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0·05, p=0·01), body-mass index (p value threshold: 0·05, p=0·00025), and blood urea nitrogen (p value threshold: 0·001, p=0·00043). The model based on six clinical predictors explained 61·4% of the variance in CLLi in cohort 1 and 49·8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59·32% to 59·36% in cohort 1 and from 49·21% to 50·03% in cohort 2 when including rs583503 and the four first principal components. INTERPRETATION: Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. FUNDING: Stanley Medical Research Institute, Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Brain Foundation, Swedish Research Council, Söderström-Königska Foundation, Bror Gadelius Minnesfond, Swedish Mental Health Fund, Karolinska Institutet and Hospital.

Shorter telomere length and suicidal ideation in familial bipolar disorder.

Bipolar Disorder (BD) has recently been related to a process of accelerated aging, with shortened leukocyte telomere length (LTL) in this population. It has also been observed that the suicide rate in BD patients is higher than in the general population, and more recently the telomere length variation has been described as shorter in suicide completers compared with control subjects. Objectives The aim of the present study was to investigate if there is an association between LTL and BD in families where two or more members have BD including clinical symptomatology variables, along with suicide behavior. Methods Telomere length and single copy gene ratio (T/S ratio) was measured using quantitative polymerase chain reaction in a sample of 143 relatives from 22 families, of which 60 had BD. The statistical analysis was performed with a polygenic mixed model. Results LTL was associated with suicidal ideation (p = 0.02) as that there is an interaction between suicidal ideation and course of the disorder (p = 0.02). The estimated heritability for LTL in these families was 0.68. In addition, covariates that relate to severity of disease, i.e. suicidal ideation and course of the disorder, showed an association with shorter LTL in BD patients. No difference in LTL between BD patients and healthy relatives was observed. Conclusion LTL are shorter in subjects with familial BD suggesting that stress related sub-phenotypes possibly accelerate the process of cellular aging and correlate with disease severity and suicidal ideation.

The Kynurenine Pathway is Differentially Activated in Children with Lyme Disease and Tick-Borne Encephalitis.

In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions.

An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation.

Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro.

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (ß = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (ß = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Prediction of lithium response using genomic data.

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

AKT1 and genetic vulnerability to bipolar disorder.

AKT1 encodes a serine/threonine kinase that has as one of its best-known substrates glycogen synthase kinase-3 (GSK3), a primary target for lithium. AKT1 has been previously been implicated as a vulnerability gene for bipolar disorder (BD). We aimed to associate genetic variants in the AKT1 gene with subgroups of BD. BD patients from a Swedish cohort (N = 831) were phenotyped in regards to their psychotic episodes according to mood-congruence in depression and manias, and compared to controls (N = 1,496). All participants were genotyped for SNPs in AKT1 previously implicated to have a role: rs3730358, rs1130214 and rs3803300. None of the effects reported in earlier studies were statistically significant, including the association between rs3803300 and BD without any psychotic symptoms, rs3803300 and mood-congruent psychosis, rs3803300 and the combined groups, as well as the association between the haplotypes formed by rs3730358 and rs1130214 and risk for BD. In a Bayesian analysis, all Bayes' Factors using default priors supported the null hypothesis in the replication set by a factor of between 5 and 1300 times. Analysis of genome wide association data did not reveal any association between BD and the AKT1 region. We conclude AKT1 is less likely to be a vulnerability gene in BD.