Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach.

BACKGROUND: Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. AIMS: To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. METHOD: This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. RESULTS: The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. CONCLUSIONS: Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

HomotopicLI: Rationale, characteristics, and implications of a new threshold-free lateralization index of functional magnetic resonance imaging.

The reliable preoperative estimation of brain hemispheric asymmetry may be achieved through multiple lateralization indices using functional magnetic resonance imaging. Adding to our previously developed AveLI, we devised a novel threshold-free lateralization index, HomotopicLI, which computes a basic formula, (Left - Right) / (Left + Right), using voxel values of pairs located symmetrically in relation to the midsagittal line as the terms Left and Right, and averages them within the regions-of-interest. The study aimed to evaluate HomotopicLI before clinical applications. Data were collected from 56 healthy participants who performed four language tasks. We compared seven index types, including HomotopicLI, AveLI, and BaseLI; BaseLI was calculated using the sums of voxel values as the terms. Contrary to our expectations, HomotopicLI performed similarly to AveLI but better than BaseLI in detecting right dominance. A detailed analysis of unilaterally activated voxels of the homotopic pairs revealed that unilateral activation occurred more frequently on the right than on the left when HomotopicLI indicated right dominance. The voxel values during right unilateral activation were smaller than those in the left, causing right dominances in the homotopic pairs by HomotopicLI. These unique features provide an advantage in detecting residual, compensative functions spreading weakly in the non-dominant hemisphere.

8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine.

INTRODUCTION: To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G). METHODS: Seventy-nine Japanese psychiatric patients were treated with MIR for 1-8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes. RESULTS: Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight-corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight-corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. DISCUSSION: The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Cognitive function, treatment response to lithium, and social functioning in Japanese patients with bipolar disorder.

OBJECTIVES: Patients with bipolar disorder often suffer from cognitive impairment that significantly influences their functional outcome. However, it remains unknown whether lithium has a central role in cognition and functional outcome. We examined whether cognition and functional outcome were predicted by demographic and clinical variables, including the response to lithium, in lithium-treated patients with bipolar disorder. METHODS: We evaluated 96 lithium-treated euthymic patients with bipolar disorder and 196 age- and-gender-matched healthy controls, using the Brief Assessment of Cognition in Schizophrenia (BACS). The patients were also assessed using the Social Functioning Scale (SFS) and "The Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" (Alda) scale, which was evaluated as either a continuous measure of the total scale or a dichotomous criterion. RESULTS: Multiple regression analysis revealed two key findings: first, that the premorbid intelligence quotient, age, and number of mood episodes were predictors of the BACS composite score; and, second, that the BACS composite score, negative symptoms, and continuous measure on the total Alda scale (but not its dichotomy) predicted the total SFS score. Structural equation modeling (SEM) was used to confirm these findings, and additionally revealed that the Alda scale was significantly associated with negative symptoms and also the number of mood episodes, regardless of how it was evaluated. CONCLUSIONS: SEM delineated how demographic and clinical variables, cognitive performance, and response to lithium treatment were causally associated with, and converged on, social function. The putative role of the Alda scale for social function warrants further study.

Multi-regression analysis revealed a relationship between l-serine and methionine, a component of one-carbon metabolism, in the normal control but not in the schizophrenia.

BACKGROUND: Alterations in one-carbon metabolism (OCM) have been observed in patients with schizophrenia (SZ), but a comprehensive study of OCM has not yet been conducted. A carbon atom is transferred from l-serine to methionine during OCM, but the relationship between l-serine and methionine in SZ is not yet known. We investigated the relationship between l-serine and methionine to obtain a comprehensive understanding of OCM in SZ. METHODS: We recruited forty-five patients with SZ and thirty normal controls (NC). Whole blood, plasma, and DNA specimens were obtained from all participants. Plasma l-serine, d-serine, glycine, methionine, and total homocysteine levels were measured using high-performance liquid chromatography. Plasma vitamin B12 and total folate were measured using a chemiluminescent protein-binding immunoassay. Clinical symptoms were estimated using the positive and negative syndrome scale (PANSS). The methylenetetrahydrofolate reductase (MTHFR) C667T genotype and A298C genotype, which are involved in MTHFR activity, were determined using the TaqMan genotyping assay system. RESULTS: Analysis of variance was used to confirm that the SZ cohort has higher plasma homocysteine levels and lower plasma folate levels than the NC group. Multi-regression analysis revealed a relationship between l-serine and methionine in the NC group but not in the SZ group. The MTHFR genotype did not affect the relationship between l-serine and methionine in each group. The total PANSS score was significantly related to d-serine and folate levels and to age. Positive PANSS scores were significantly related to both glycine and sex. In addition, both glycine and d-serine were significantly correlated with negative PANSS scores. CONCLUSIONS: We found impairment of the relationship between l-serine and methionine in SZ. Clinical symptoms of SZ were partially correlated with the OCM components. These findings contributed to our understanding of OCM alteration in SZ and may explain why the alteration occurs.

Effects of background mutations and single nucleotide polymorphisms (SNPs) on the Disc1 L100P behavioral phenotype associated with schizophrenia in mice.

BACKGROUND: Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene for psychiatric disorders, including schizophrenia, bipolar disorder and major depression. Several previous studies reported that mice with N-ethyl-N-nitrosourea (ENU)-induced L100P mutation in Disc1 showed some schizophrenia-related behavioral phenotypes. This line originally carried several thousands of ENU-induced point mutations in the C57BL/6 J strain and single nucleotide polymorphisms (SNPs) from the DBA/2 J inbred strain. METHODS: To investigate the effect of Disc1 L100P, background mutations and SNPs on phenotypic characterization, we performed behavioral analyses to better understand phenotypes of Disc1 L100P mice and comprehensive genetic analyses using whole-exome resequencing and SNP panels to map ENU-induced mutations and strain-specific SNPs, respectively. RESULTS: We found no differences in spontaneous or methamphetamine-induced locomotor activity, sociability or social novelty preference among Disc1 L100P/L100P, L100P/+ mutants and wild-type littermates. Whole-exome resequencing of the original G1 mouse identified 117 ENU-induced variants, including Disc1 L100P per se. Two females and three males from the congenic L100P strain after backcrossing to C57BL/6 J were deposited to RIKEN BioResource Center in 2008. We genotyped them with DBA/2 J × C57BL/6 J SNPs and found a number of the checked SNPs still remained. CONCLUSION: These results suggest that causal attribution of the discrepancy in behavioral phenotypes to the Disc1 L100P mutant mouse line existing among different research groups needs to be cautiously investigated in further study by taking into account the effect(s) of other ENU-induced mutations and/or SNPs from DBA/2 J.

Simultaneous determination of N(G)-monomethyl-L-arginine, N(G),N(G)-dimethyl-L-arginine, N(G),N(G')-dimethyl-L-arginine, and L-arginine using monolithic silica disk-packed spin columns and a monolithic silica column.

We have developed and validated a high-performance liquid chromatography method that uses monolithic silica disk-packed spin columns and a monolithic silica column for the simultaneous determination of N(G)-monomethyl-L-arginine, N(G),N(G)-dimethyl-L-arginine, and N(G),N(G')-dimethyl-L-arginine in human plasma. For solid-phase extraction, our method employs a centrifugal spin column packed with monolithic silica bonded to propyl benzenesulfonic acid as a cation exchanger. After pretreatment, the methylated arginines are converted to fluorescent derivatives with 4-fluoro-7-nitro-2,1,3-benzoxadiazole, and then the derivatives are separated on a monolithic silica column. L-arginine concentration was also determined in diluted samples. Standard calibration curves revealed that the assay was linear in the concentration range 0.2-1.0 µM for methylated arginines and 40-200 µM for L-arginine. Linear regression of the calibration curve yielded equations with correlation coefficients of 0.999 (r(2)). The sensitivity was satisfactory, with a limit of detection ranging from 3.75 to 9.0 fmol for all four compounds. The RSDs were 4.3-4.8% (intraday) and 3.0-6.8% (interday). When this method was applied to samples from six healthy donors, the detected concentrations of N(G)-monomethyl-L-arginine, N(G),N(G)-dimethyl-L-arginine, N(G),N(G')-dimethyl-L-arginine and L-arginine were 0.05 ± 0.01, 0.41 ± 0.07, 0.59 ± 0.11, and 83.8 ± 30.43 µM (n = 6), respectively.

Activation of prefrontal parvalbumin interneurons ameliorates working memory deficit even under clinically comparable antipsychotic treatment in a mouse model of schizophrenia.

One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2-3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60-80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.

Associations among plasma markers for N-methyl-d-aspartate receptor hypofunction, redox dysregulation, and insufficient myelination in patients with schizophrenia.

Background: Several hypotheses regarding the pathomechanisms of schizophrenia have been proposed. If schizophrenia is a unitary disease, then these pathological processes must be linked; however, if such links do not exist, schizophrenia may best be considered a group of disorders. Only a few studies have examined the relationships among these pathomechanisms. Herein, we examined the relationships among deficient myelination, NMDA receptor hypofunction, and metabolic dysregulation by measuring various plasma markers and examining their correlations. Methods: Plasma samples were collected from 90 patients with schizophrenia and 68 healthy controls. Concentrations of nardilysin (N-arginine dibasic convertase, NRDC), a positive regulator of myelination, the NMDA receptor co-agonist d-serine and glycine, various additional amino acids related to NMDA receptor transmission (glutamate, glutamine, and l-serine), and homocysteine (Hcy), were measured. Concentrations were compared using independent samples t-test or logistic regression, and associations were evaluated using Pearson's correlation coefficients. Results: Plasma glycine (t = 2.05, p = 0.042), l-serine (t = 2.25, p = 0.027), and homocysteine (t = 3.71, p < 0.001) concentrations were significantly higher in patients with schizophrenia compared to those in healthy controls. Logistic regression models using age, sex, smoking status, glutamine, glutamate, glycine, l-serine, d-serine, homocysteine, and NRDC as independent variables revealed significantly lower plasma d-serine (p = 0.024) and NRDC (p = 0.028), but significantly higher l-serine (p = 0.024) and homocysteine (p = 0.001) in patients with schizophrenia. Several unique correlations were found between NMDA receptor-related amino acids and NRDC in patients with schizophrenia compared to those in healthy controls, while no correlations were found between plasma homocysteine and other markers. No associations were found between plasma marker concentrations and disease status or cognitive function in patients with schizophrenia, except for a significant correlation between plasma glycine and full intelligence quotient. Conclusion: Reduced myelination and NMDA receptor hypofunction may be related to pathological mechanisms in schizophrenia, while homocysteine dysregulation appears to be an independent pathological process. These results suggest that schizophrenia may be a group of disorders with unique or partially overlapping etiologies.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Exploring the genetics of lithium response in bipolar disorders.

BACKGROUND: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. RESULTS: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. CONCLUSIONS: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Association of the Hermansky-Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects.

BACKGROUND: The Hermansky-Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; however, its clinical relevance in schizophrenia remains unknown. The purpose of the present study was to investigate whether HPS4 is associated with cognitive functions in patients with schizophrenia and healthy controls and with the clinical profiles of patients with schizophrenia. METHODS: We investigated the association of variants of HPS4 with clinical symptoms and cognitive function in Japanese patients with schizophrenia (n = 240) and age-matched healthy control subjects (n = 240) with single nucleotide polymorphisms (SNP)- or haplotype-based linear regression. We analyzed five tagging SNPs (rs4822724, rs61276843, rs9608491, rs713998, and rs2014410) of HPS4 and 2-5 locus haplotypes of these five SNPs. The cognitive functions of patients and healthy subjects were evaluated with the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, and the patients were assessed for their symptomatology with the Positive and Negative Symptom Scale (PANSS). RESULTS: In patients with schizophrenia, rs713998 was significantly associated with executive function under the dominant genetic model (P = 0.0073). In healthy subjects, there was a significant association between working memory and two individual SNPs under the recessive model (rs9608491: P = 0.001; rs713998: P = 0.0065) and two haplotypes (rs9608491-713998: P = 0.0025; rs61276843-9608491-713998: P = 0.0064). No significant association was found between HPS4 SNPs and PANSS scores or premorbid IQ, as measured by the Japanese version of the National Adult Reading Test. CONCLUSIONS: These findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3ß. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Exploring the genetics of lithium response in bipolar disorders.

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.