Etiology Of Bipolar Disorder Research Articles

Refining criteria for a neurodevelopmental sub-phenotype of bipolar disorders: a FondaMental Advanced Centers of Expertise for Bipolar Disorders study

Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. Neurodevelopmental factors were suggested to contribute to the etiology of BD, yet a specific neurodevelopmental phenotype of the disorder remains unidentified. Our objective was to define and characterize a neurodevelopmental phenotype (NDP) in BD and validate its associations with clinical outcomes, polygenic risk scores (PGS), and treatment responses. We analyzed the FACE-BD cohort of 4,468 BD patients, a validation cohort of 101 BD patients, and two independent replication datasets of 274 and 89 BD patients. Using factor analyses, we identified a set of criteria for defining NDP. We next developed a scoring system for NDP-load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and sex with bootstrap replications. Our study established a NDP in BD consisting of nine clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention deficit hyperactivity disorder (ADHD), early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, specific learning disorders. Patients with higher NDP-load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between the NDP-load and PGS for ADHD suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and ADHD. The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

Single-cell multiomics analysis reveals cell/tissue-specific associations in bipolar disorder

This study investigates the cellular origin and tissue heterogeneity in bipolar disorder (BD) by integrating multiomics data. Four distinct datasets were employed, including single-cell RNA sequencing (scRNA-seq) data (embryonic and fetal brain, n = 8, 1,266 cells), BD Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) data (adult brain, n = 210), BD bulk RNA-seq data (adult brain, n = 314), and BD genome-wide association study (GWAS) summary data (n = 413,466). The integration of scRNA-seq data with multiomics data relevant to BD was accomplished using the single-cell disease relevance score (scDRS) algorithm. We have identified a novel brain cell cluster named ADCY1, which exhibits distinct genetic characteristics. From a high-resolution genetic perspective, glial cells emerge as the primary cytopathology associated with BD. Specifically, astrocytes were significantly related to BD at the RNA-seq level, while microglia showed a strong association with BD across multiple panels, including the transcriptome-wide association study (TWAS), ATAC-seq, and RNA-seq. Additionally, oligodendrocyte precursor cells displayed a significant association with BD in both ATAC-seq and RNA-seq panel. Notably, our investigation of brain regions affected by BD revealed significant associations between BD and all three types of glial cells in the dorsolateral prefrontal cortex (DLPFC). Through comprehensive analyses, we identified several BD-associated genes, including CRMP1, SYT4, UCHL1, and ZBTB18. In conclusion, our findings suggest that glial cells, particularly in specific brain regions such as the DLPFC, may play a significant role in the pathogenesis of BD. The integration of multiomics data has provided valuable insights into the etiology of BD, shedding light on potential mechanisms underlying this complex psychiatric disorder.

Longitudinal changes in resting-state functional connectivity as markers of vulnerability or resilience in first-degree relatives of patients with bipolar disorder.

There is a significant contribution of genetic factors to the etiology of bipolar disorder (BD). Unaffected first-degree relatives of patients (UR) with BD are at increased risk of developing mental disorders and may manifest cognitive impairments and alterations in brain functional and connective dynamics, akin to their affected relatives. In this prospective longitudinal study, resting-state functional connectivity was used to explore stable and progressive markers of vulnerability i.e. abnormalities shared between UR and BD compared to healthy controls (HC) and resilience i.e. features unique to UR compared to HC and BD in full or partial remission (UR n = 72, mean age = 28.0 ± 7.2 years; HC n = 64, mean age = 30.0 ± 9.7 years; BD patients n = 91, mean age = 30.6 ± 7.7 years). Out of these, 34 UR, 48 BD, and 38 HC were investigated again following a mean time of 1.3 ± 0.4 years. At baseline, the UR showed lower connectivity values within the default mode network (DMN), frontoparietal network, and the salience network (SN) compared to HC. This connectivity pattern in UR remained stable over the follow-up period and was not present in BD, suggesting a resilience trait. The UR further demonstrated less negative connectivity between the DMN and SN compared to HC, abnormality that remained stable over time and was also present in BD, suggesting a vulnerability marker. Our findings indicate the coexistence of both vulnerability-related abnormalities in resting-state connectivity, as well as adaptive changes possibly promoting resilience to psychopathology in individual at familial risk.

Influence of genetic background on the clinical picture of bipolar affective disorder in a population of children and adolescents

IntroductionBipolar disorder in children is characterized by a different course than in adults, which is a diagnostic difficulty. DAT-1 is a dopamine transporter gene that regulates dopaminergic neurotransmission through the mechanism of active reuptake of this neurotransmitter from the synapse. Polymorphisms within the described gene can result in changes in dopamine levels, which may have implications for the development of bipolar disorder.Objectives The aim of the project was to analyze the relationship between single nucleotide polymorphisms (SNPs) within the dopamine transporter gene DAT-1 and the risk of development of bipolar disorder in a population of children and adolescents.Methods21 healthy controls (12 females, 9 males) have been recruited into the study and 13 patients (9 girls, 4 boys) with bipolar disorder diagnosis from Department of Psychiatry and outpatient clinic, were recruited for the study group. Questionnaires such as the KSADS-PL were carried out and blood was taken for laboratory tests of four SNPs within the DAT-1 transporter. PQStat, Microsoft Excel 2013 and StatSoft STATISTICA were used to perform the statistical analysis.ResultsSNPs within the dopamine transporter gene and environmental risk factors influenced the risk of developing bipolar disorder in the population of children and adolescents.ConclusionsThe ambiguity in results emphasizes the necessity for further investigations into correlation between genetic factors in bipolar disorder etiology. Future research should involve more participants. The results of this project are likely to make a significant and valuable contribution to the current knowledge of bipolar disorder and to the development of innovative diagnostic methods, making a significant contribution to the advancement of science.Disclosure of InterestNone Declared

Marked alteration of phosphoinositide signaling-associated molecules in postmortem prefrontal cortex with bipolar disorder.

The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3β (GSK3β), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD. The protein expression levels of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), phosphatidylinositol 4-kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3β were measured using enzyme-linked immunosorbent assays and multiplex fluorescent bead-based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3β, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls. PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3β were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group. Our results suggest that the expression levels of Akt1/GSK3β and its upstream regulator PTEN are considerably altered.

Interplay between polygenic risk for mood disorders and stressful life events in bipolar disorder

BackgroundAlthough genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. MethodsThis study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. ResultsFor the worst depressive episode, the PRS-MDD was significantly correlated with total number of SLEs (β = 0.13, 95 % CI:0.04–0.22, p = 0.003) and dependent SLEs (β = 0.09, 95 % CI:0.02–0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (β = 0.11, 95 % CI:0.02–0.20, p = 0.015) and dependent SLEs (β = 0.08, 95 % CI:0.01–0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: β = 0.19, 95 % CI:0.04–0.35, p = 0.015; PRS-BD: β = 0.16, 95 % CI:0.01–0.32, p = 0.042) and dependent SLEs (PRS-MDD: β = 0.14, 95 % CI:0.03–0.26, p = 0.015; PRS-BD: β = 0.12, 95 % CI:0.004–0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. LimitationsUse of a larger sample size would be beneficial. ConclusionsThe relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.

Linking the gut microbiota to brain dysfunction in bipolar disorder: Evidence from neuroimaging

The gut microbiota can influence the brain function through a variety of ways, but its role in the etiology of Bipolar Disorder (BD) is yet unknown. The brain and the gut are linked through a communication pathway called the Microbiota-Gut-Brain Axis (MGBA).

Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca2+ entry and accelerated differentiation

While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca2+) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca2+ entry (SOCE) is not well understood. Here, we report Ca2+ and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons. First, using a Ca2+ re-addition assay we found that BD-NPCs and neurons had attenuated SOCE. Intrigued by this finding, we then performed RNA-sequencing and uncovered a unique transcriptome profile in BD-NPCs suggesting accelerated neurodifferentiation. Consistent with these results, we measured a slower rate of proliferation, increased neurite outgrowth, and decreased size in neurosphere formations with BD-NPCs. Also, we observed decreased subventricular areas in developing BD cerebral organoids. Finally, BD NPCs demonstrated high expression of the let-7 family while BD neurons had increased miR-34a, both being microRNAs previously implicated in neurodevelopmental deviations and BD etiology. In summary, we present evidence supporting an accelerated transition towards the neuronal stage in BD-NPCs that may be indicative of early pathophysiological features of the disorder.

The Role of Early Toxic Interaction with Fathers in Males with Bipolar Spectrum Disorder

Purpose: The etiology of bipolar disorder (BD), a most debilitating mental illness worldwide, focuses on childhood traumatic experiences, some concerning parents. This study explored the role of early toxic interaction with fathers in males with BD.Methods: This qualitative study used a descriptive phenomenological approach and purposive sampling in Tehran, Iran, in 2022. The data were generated through 12 semi-structured interviews with males with BD who visited psychiatric centers in Tehran, Iran. The interviews continued until data saturation. The collected data were analyzed using Colaizzi’s seven-step method.Results: The data revealed thirteen subthemes comprising three main themes: the experience of living in constant neglect and rejection, living with fear and abandonment, and reflection of the father’s past interactive patterns in the son’s life.Conclusion: Living in neglect, fear, and abandonment, and repeating past interactive patterns in current life were some of the bitter life experiences of men with BD, who considered the problematic relationship and misbehavior of their fathers to be somewhat effective in the formation of their life problems, but reported that they could not help themselves with personal and social adaptation. Individual and supportive psychotherapies with drug therapy can help the rehabilitation and recovery of these patients.

Evaluation of Serum Zonulin and Occludin Levels in Bipolar Disorder.

The etiology of bipolar disorder (BD) is still not fully understood. Little is currently known about the relationship between the interaction the gastrointestinal system and brain function and BD. Zonulin is the only known physiological modulator of tight junctions and is a biomarker for intestinal permeability (IP). Occludin is an integral transmembrane tight junction protein involved in the maintenance and assembly of such junctions. The current study aims to determine whether zonulin and occludin levels are altered in BD and whether they can serve as clinical biomarkers of disease. Forty-four patients with BD and 44 healthy controls were included in this study. The Young Mania Rating Scale (YMRS) was used to determine the severity of manic symptoms, while the Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depressive symptoms, and the Brief Functioning Rating Scale (FAST) to assess functionality. Venous blood samples were taken from all participants and serum zonulin and occludin levels were measured. The mean serum zonulin and occludin levels of the patients were significantly higher compared to the healthy control group. There was no difference between manic, depressive, and euthymic patients in terms of zonulin and occludin levels. There was no correlation between the total number of attacks, duration of disease, YMRS, HDRS, FAST scores, and zonulin and occludin levels in the patient group. The groups were divided into three according to body mass index as normal, overweight, and obese. Zonulin and occludin levels increased as body mass index increased and were highest in the obese group. The study shows that zonulin and occludin levels in BD increase independently of the disease stage. Consideration of the role of IP in the pathogenesis of BD may be helpful in determining the appropriate treatment modality.

Statistical and Functional Fine-Mapping as a Powerful Tool to Unravel the Biological Etiology of Bipolar Disorder

Statistical and Functional Fine-Mapping as a Powerful Tool to Unravel the Biological Etiology of Bipolar Disorder

Assessment of serum high mobility group box 1 protein (HMGB1) levels and its change with treatment in patients with manic episode of bipolar disorder

IntroductionThere has been an increasing evidence in recent years that inflammation plays a role in the pathophysiology of bipolar disorder (BD). In addition to central inflammation, systemic immune response is thought to be associated with disease stages and course. HMGB1 protein is a member of damage-associated molecular pattern which plays a role in the regulation of cytokine release and is important for innate immunity. It has been revealed that HMGB1 levels change in many autoimmun and inflammatory diseasesObjectivesOur study was designed to compare serum HMGB1 levels of inpatients with mania and healthy controls as well as analyzing its relationship with other inflammatory markers and disease severity. Another aim of our study is to determine the changes in serum HMGB1 levels before and after treatment in manic patients.MethodsOur study included 35 patients who were hospitalized in our hospital between November 2020 and April 2021, diagnosed with bipolar disorder, manic episode according to DSM-5 criteria, and 35 healthy controls who matched to the patient group in terms of age and gender. The sociodemographic and clinical characteristics data forms of the participants were filled in, and the patients were evaluated with the Young-Mania Rating Scale (YMRS) and the Hamilton Depression Scale (HAM-D). Serum HMGB1, CRP levels and complete blood count values were measured in healthy controls and patients before and after the treatment.ResultsThe main finding of our study is that HMGB1 levels did not show a statistically significant difference in the patient and healthy control groups (p>0.05). In addition, there was no significant change in serum HMGB1 levels of the patients after treatment compared to the level before treatment (p>0.05). Our study has also revealed that manic patients had a higher level of CRP than the ones in control group at a statistically significant level. The platelet/lymphocyte and neutrophil/lymphocyte rates of the patients increased after the treatment compared to the pre-treatment period (respectively p=0,026, p=0,003).ConclusionsThe higher CRP levels in manic patients support the hypothesis of low-grade chronic inflammation, which is thought to be involved in the etiology of BD. The most important finding of this study is that there is no statistically significant difference of serum HMGB1 levels between the two groups. This can be explained by the fact that HMBG1 is one of the late mediators of inflammation and does not rise immediately during the acute period. However, since the inflammation process includes complex mechanisms involving many systems, it makes it difficult to comment on this issue.Disclosure of InterestNone Declared

Are bipolar disorder, major depression, and suicidality linked with Toxoplasma gondii? A seromolecular case-control study

ABSTRACT Objective The existence of predisposing effects of latent Toxoplasma gondii (T. gondii) infection in bipolar disorder (BD), major depression (MD), and even suicide attempt (SA) has long been debatable. This conjecture remains unclear because there is a lack of evidence regarding how T. gondii manipulates the brain and behavior. Methods We investigated the influence of T. gondii infection on BD and MD patients with or without SA compared to age-, sex-, and province-matched healthy controls (HCs) concurrently with serology and molecular-based evaluations. We prospectively assessed 147 volunteers with BD, 161 with MD, and 310 HCs. Results T. gondii seropositivity rates were 57.1% for BD, 29.2% for MD, 64.8% for SA, and 21.3% for HC. Binary logistic regression analyses revealed that T. gondii positive Immunoglobulin G (IgG) status may be a prominent tendentious agent for BD (OR = 3.52; 95% CI [2.19–5.80]; p < 0.001) and SA (OR = 17.17; 95% CI [8.12–36.28]; p < 0.001), but not for MD (OR = 1.21; 95% CI [0.74–1.99]; p = 0.45). Nevertheless, the T. gondii DNA ratios determined by polymerase chain reaction (PCR) were linked to BD and MD. Conclusion Our findings strongly support the burgeoning interest in the possibility that latent T. gondii infection may be relevant to the etiology of BD and SA, although this connection remains ambiguous.

High Mobility Group Box 1 Levels as an Inflammatory Mediator in Bipolar Mania.

High mobility group box 1 protein (HMGB1) is a member of the molecular family known as damage-associated molecular patterns, which is implicated to have a role in neuroinflammation processes. In recent years, a growing number of studies have focused on the role of inflammation in Bipolar Disorder (BD). This study aimed to investigate the serum levels of HMGB1 and other inflammatory markers in patients with bipolar manic episodes compared to those in healthy controls (HC). A single-center, observational, case-control study was conducted. Thirty-five patients with BD in manic episodes and 35 HC were assessed. Young Mania Rating Scale (YMRS) was used to assess the symptom severity of the patient group. While inflammatory markers (such as HMGB1, C-reactive protein (CRP) and white blood cell count) were assessed at the first three and the last day of hospitalization in the patient group, they were evaluated once in HC. Levels of inflammatory markers were compared between (patient-HC) and within groups (before-after treatment). No difference was observed in serum HMGB1 levels of bipolar patients with manic episodes compared to the HC (p>0.05). C-reactive protein levels of manic patients were higher than HC (p<0.001), and the difference persisted even after treatment (p=0.007). In addition, there was a significant positive correlation between CRP levels and antipsychotic drug dosage (r=0.382, p=0.024). There were no differences in HMGB1 levels between bipolar patients with acute manic episode and HC. However, higher CRP levels in bipolar patients support the low-grade inflammation hypothesis in the etiology of BD.

Vanadium in Bipolar Disorders-Reviving an Old Hypothesis.

Bipolar disorder (BD) is a severe and common chronic mental illness. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Our previous studies supported the notion that alterations in Na+, K+-ATPase activity were involved in the etiology of BD. As various chemical elements inhibit Na+, K+-ATPase, we determined the concentration of 26 elements in the serum of BD patients before and after treatment and in postmortem brain samples from BD patients, and compared them with matched controls. The only element that was reduced significantly in the serum following treatment was vanadium (V). Furthermore, the concentration of V was significantly lower in the pre-frontal cortex of BD patients compared with that of the controls. Intracerebroventricular administration of V in mice elicited anxiolytic and depressive activities, concomitantly inhibited brain Na+, K+-ATPase activity, and increased extracellular signal-regulated kinase phosphorylation. A hypothesis associating V with BD was set forth decades ago but eventually faded out. Our results are in accord with the hypothesis and advocate for a thorough examination of the possible involvement of chemical elements, V in particular, in BD.

MicroRNAs, Stem Cells in Bipolar Disorder, and Lithium Therapeutic Approach.

Bipolar disorder (BD) is a severe, chronic, and disabling neuropsychiatric disorder characterized by recurrent mood disturbances (mania/hypomania and depression, with or without mixed features) and a constellation of cognitive, psychomotor, autonomic, and endocrine abnormalities. The etiology of BD is multifactorial, including both biological and epigenetic factors. Recently, microRNAs (miRNAs), a class of epigenetic regulators of gene expression playing a central role in brain development and plasticity, have been related to several neuropsychiatric disorders, including BD. Moreover, an alteration in the number/distribution and differentiation potential of neural stem cells has also been described, significantly affecting brain homeostasis and neuroplasticity. This review aimed to evaluate the most reliable scientific evidence on miRNAs as biomarkers for the diagnosis of BD and assess their implications in response to mood stabilizers, such as lithium. Neural stem cell distribution, regulation, and dysfunction in the etiology of BD are also dissected.

Understanding the Developmental Pathways and Onset of Bipolar Disorder and Borderline Personality Disorder in Young People: A Systematic Review of Reviews

AimsThere is still an ongoing debate on the nosological position of Bipolar Disorder (BD) and Borderline Personality Disorder (BPD). Identifying the unique and shared risks and developmental pathways in emerging BD and BPD could help the field refine aetiological hypotheses of these disorders. The study aims were to systematically synthesise the available evidence from systematic reviews and meta-analyses concerning environmental, psychosocial, biological, and clinical factors leading to the emergence of BD and BPD to identify the main differences and common characteristics between the two disorders to characterise their complex interplay whilst highlighting remaining evidence gaps.MethodsA literature search was conducted PubMed, PsychINFO, EMBASE, Cochrane, CINAHL, MEDLINE, and ISI Web of Science as the data sources. 19 systematic reviews and meta-analyses involving 217 prospective studies met eligibility criteria.ResultsResults demonstrated that family history of psychopathology, affective instability, attention deficit hyperactivity disorder, anxiety disorders, depression, sleep disturbances, substance abuse, psychotic symptoms, suicidality, childhood adversity and temperament dimensions were common predisposing factors across both disorders. There are also many distinct variables that could be found early in the course of both disorders. Most of the factors should be considered as a general, nonspecific precursor signs and symptoms of both BPD and BD, apart from subsyndromal depression, subsyndromal hypomania, cyclothymia disorder, psychotic symptoms, age at onset of major depression and frequency and loading of affective symptoms.ConclusionAlthough the findings of this review may lead to support the view of BD and BPD as two distinct disorders, there is not sufficient data to either indicate that BD and BPD are separate nosological entities or that BPD should be considered as an extension of BD disorders. Future research is required to increase our understanding of the aetiology of BD and BPD onset and their complex interplay by conducting prospective studies which concurrently examine multiple measures including biological, environmental, psychosocial and clinical factors in BD and BPD at-risk populations. Large, multilevel data sets will enable deep phenotyping and distinguish pathophysiological pathways.

Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers.

Bipolar disorder is a mental illness that causes extreme mood swings and has a chronic course. However, the mechanism by which mood episodes with completely opposite characteristics appear repeatedly, or a mixture of symptoms appears, in patients with bipolar disorder remains unknown. Therefore, mood stabilizers are indicated only for single mood episodes, such as manic episodes and depressive episodes, and no true mood-stabilizing drugs effective for treating both manic and depressive episodes currently exist. Therefore, in this review, therapeutic targets that facilitate the development of mood stabilizers were examined by reviewing the current understanding of the neuromolecular etiology of bipolar disorder.

Haplotype phasing of a bipolar disorder pedigree revealed rare multiple mutations of SPOCD1 gene in the 1p36–35 susceptibility locus

BackgroundThe etiology of bipolar disorder (BD) is poorly understood. Considering the complexity of BD, pedigree-based sequencing studies focusing on haplotypes at specific loci may be practical to discover high-impact risk variants. This study comprehensively examined the haplotype sequence at 1p36–35 BD and recurrent depressive disorder (RDD) susceptibility loci. MethodsWe surveyed BD families in Okinawa, Japan. We performed linkage analysis and determined the phased sequence of the affected haplotype using whole genome sequencing. We filtered rare missense variants on the haplotype. For validation, we conducted a case-control genetic association study on approximately 3000 Japanese subjects. ResultsWe identified a three-generation multiplex pedigree with BD and RDD. Strikingly, we identified a significant linkage with mood disorders (logarithm of odds [LOD] = 3.61) at 1p36–35, supported in other ancestry studies. Finally, we determined the entire sequence of the 6.4-Mb haplotype shared by all affected subjects. Moreover, we found a rare triplet of missense variants in the SPOCD1 gene on the haplotype. Notably, despite the rare frequency, one heterozygote with multiple SPOCD1 variants was identified in an independent set of 88 BD type I genotyping samples. LimitationsThe 1p36–35 sequence was obtained from only a single pedigree. The replicate sample was small. Short-read sequencing might miss structural variants. A polygenic risk score was not analyzed. ConclusionThe 1p36–35 haplotype sequence may be valuable for future BD variant studies. In particular, SPOCD1 is a promising candidate gene and should be validated.

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.