Focused Ion Beam (FIB) has been used to create single α-β colony micro-pillars from a polycrystalline commercial Ti-6Al-4V (Ti-64) sample. Each pillar was selected to have either a single alpha phase, a single beta phase, or two α lamella separated by a thin β phase filet. Then, utilizing a diamond flat tip as a compression platen, uniaxial micro-compression tests were performed on the single crystal α and β pillars as well as a tri-crystal α/β/α pillar using a nano-indenter. Then, utilizing a diamond flat tip as a compression platen, uniaxial micro-compression tests were performed on the single crystal alpha and beta pillars as well as a tri-crystal α/β/α pillar using a nano-indenter. Through the use of Electron Back Scattering Diffraction (EBSD) to choose the crystal orientation along the micro-pillar, three distinct unique slip systems have been selectively triggered by maximizing the Schmid factor for each system. The potential to localize a single crystal volume that can be characterized after deformation is one benefit of the micro-compression approach over traditional mechanical testing. The sample strengths compare well with published data. The mechanical properties of the α-β colonies and the single α and β phases have been compared in order to elucidate the role of the α/β interfaces in determining the critical resolved shear stress.

Rare copy number variants (CNVs) are a key component of the genetic basis of psychiatric conditions, but have not been well characterized for most. We conducted a genome-wide CNV analysis across six diagnostic categories (N = 574,965): autism (ASD), ADHD, bipolar disorder (BD), major depressive disorder (MDD), PTSD, and schizophrenia (SCZ). We identified 35 genome-wide significant associations at 18 loci, including novel associations in SCZ ( SMYD3, USP7 - HAPSTR1 ) and in the combined cross-disorder analysis ( ASTN2 ). Rare CNVs accounted for 1-3% of heritability across diagnoses. In ASD, associations were uniformly positive, consistent with autism having diverse etiologies and clinical presentations. By contrast, CNVs showed a dose-dependent relationship for other diagnoses, including SCZ and PTSD, with reciprocal deletions and duplications having inversely correlated effects and distinct genotype-phenotype relationships. Our findings suggest that genes have effects that are both dose-dependent and pleiotropic, such that a positive influence on one dimension of psychopathology may be accompanied by positive or negative effects on others.

Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline.

Postpartum psychosis (PP) is an acute and severe psychiatric illness with onset within weeks after delivery and a high risk of suicide and infanticide. Most women with PP experience severe mood symptoms, including mania, mixed episodes, or depression with psychotic features. Impaired cognition, irritability, and agitation are also common. The specific timing of PP strongly suggests a biological basis, because the postpartum time period is characterized by profound endocrine, immune, neuroanatomical, and physiological changes in the brain. Genetic studies show a unique risk architecture, partly shared with bipolar disorder. PP stands out as one of the most distinct clinical phenotypes in psychiatry due to its characteristic rapid onset, severity, phenomenology, treatment response, and prognosis. Despite this, as of August 2025, PP does not have a distinct diagnostic classification in the DSM. This expert consensus panel, in close collaboration with patient organizations and key interested partners, recommends classifying PP as a distinct category within DSM-5 and ICD-11. We recommend classification within the bipolar disorders chapter of the DSM because 1) most women with PP have prominent affective symptoms; 2) treatment response to lithium and electroconvulsive therapy is excellent; 3) in half of the cases, first-onset PP is also the first onset of bipolar disorder; 4) pregnant women with bipolar disorder are at very high risk of PP; and 5) the genetic risk architecture for PP is distinct but overlapping with bipolar disorder. This consensus statement summarizes scientific evidence that PP is a distinct mental illness within the bipolar spectrum; correct classification will improve detection and treatment.

Background Postpartum psychosis is the most severe postpartum mental illness, affecting 1-2 in every 1000 childbirths. Research into the causes and risk factors of postpartum psychosis has been impeded by confusion around its classification. Recent evidence suggests that the genetic architecture of postpartum psychosis differs from that of bipolar disorder. This work aimed to explore this further. Methods Cases were ascertained through the Bipolar Disorder Research Network (BDRN), who were assessed using semi-structured interviews and case note review. Postpartum psychosis was defined as a manic, mixed, or psychotic depression episode within 6 weeks of delivery. Healthy female controls were recruited through the national UK Blood Services, the 1958 British Birth Cohort (UK National Child Development Study) and the UK Household Longitudinal Study. The total sample size for the genome-wide association study was 772 cases and 8,537 controls. Heritability was estimated using LDAK with restricted maximum likelihood. Genetic correlations with schizophrenia and major depression were conducted using Linkage Disequilibrium Score Regression (LDSC). Muti-marker Analysis of GenoMic Annotation (MAGMA) through the online tool Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA) was used to identify independent lead SNPs and conduct functional gene mapping. Results No genome-wide significant SNPs were identified, however, several were suggestive at a genome-wide significance level of p < 1 × 10-5. These mapped onto 13 genetic loci and 23 genes. No significant enrichment was found for any gene sets or specific tissues. SNP heritability for postpartum psychosis was estimated to be 0.54 (SE: 0.038). Genetic correlation with bipolar type-I was high (0.57, SE: 0.11, p = 5.18 × 10-8) but significantly different from 1 (p = 9.26 × 10-5). Genetic correlation with schizophrenia was similarly high (0.55, SE: 0.10, p = 1.84 × 10-8) and lower for bipolar type-II and major depression (0.31, SE: 0.17, p = 0.061; 0.34, SE: 0.15, p = 0.029). Discussion These results suggest substantial genetic overlap between postpartum psychosis and bipolar type-I and schizophrenia. They also provide evidence for the genetic architecture of postpartum psychosis being partially distinct from bipolar disorder. This supports previous literature and advocates for postpartum psychosis being included as its own distinct entity within diagnostic manuals.

Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

Importance:The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. Objective:To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. Design Setting and Participants:This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for. Main Outcomes and Measures:The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h 2 SNP ), genetic correlations, genomic loci ( P ≤5×10 -8 ), and functional, cell-type, and gene-expression pathway analyses. Results:We identified four genetically-informed dimensions of BD: Severe Illness, Core Mania, Externalizing/Impulsive Comorbidity, and Internalizing/Affective Comorbidity. The analyses yielded up to 181 subphenotype-associated loci, 53 of which are novel. The Severe Illness Dimension was characterized by a unique neuro-immune signature (a protective association with HLA-DMB , P =2.50×10 -273 ) evident only when leveraging SCZ genetic data. The Internalizing/Affective dimension was associated with neurodevelopmental genes (e.g., DCC ). Notably, the rapid-cycling subphenotype showed a unique signature of strong negative selection, a finding not observed in other subphenotypes. Conclusions and Relevance:The clinical heterogeneity of bipolar disorder appears to be defined by a complex and multi-layered genetic architecture. The presented findings provide an empirical framework that may advance psychiatric nosology beyond its current diagnostic boundaries. These results may also inform future research to identify targets for personalized interventions. The delineation of these genetically-informed dimensions offers specific, biologically-grounded hypotheses for subsequent therapeutic discovery. Establishing such a framework is an essential step toward refining diagnostic criteria and developing more effective, personalized treatments. This work lays the foundation for a transition from a uniform treatment model to the paradigm of precision psychiatry. Key Points:Question: What are the distinct genetic architectures underlying the clinical heterogeneity of bipolar disorder?Findings: In this genetic study of 23,819 bipolar disorder (BD) cases and 163,839 controls, clinical heterogeneity mapped onto four genetically-informed dimensions. A severe illness dimension was defined by a neuro-immune signature ( HLA-DMB ) shared with schizophrenia. An affective comorbidity dimension was distinguished by neurodevelopmental pathways involving axonal guidance ( DCC ). Notably, the rapid-cycling phenotype showed evidence of purifying selection, suggesting influence by rare, highly penetrant alleles. Meaning: These findings provide a data-driven biological framework for bipolar disorder, guiding future research toward patient stratification and targeted therapeutics.

BACKGROUND:No published research into perinatal mood episodes (PMEs) among fathers with bipolar disorder (BD) exists despite the perinatal period being a time of high-risk for mothers with BD. This study aims to determine the frequency, polarity and timing of onset of PMEs in a large sample of fathers with BD. METHOD:Data on PMEs were collected from 196 fathers with a DSM diagnosis of BD. Participants were asked via a self-report questionnaire about the occurrence, type and timing of PMEs during pregnancy up to 6 months postpartum. Findings were compared to data on PMEs collected from mothers with BD using the same method (n = 597). RESULTS:36.2 % of fathers with BD reported experiencing PMEs, with similar proportions reporting depression and high/mixed mood/psychosis (17 % and 18.6 % respectively). Episode onset was most common during pregnancy (41.9 %) (compared to within 1-week, 1 to 6-weeks, and 6 weeks to 6 months postpartum respectively). Rate of PME in mothers was higher (73.0 %), with high/mixed mood/psychosis more common than depression (44.5 % v 28.1 %), and most common onset within 1-week postpartum (41.3 %). LIMITATIONS:Rates of paternal PMEs in BD in this study are likely inflated due to methodology. CONCLUSIONS:PMEs were commonly reported among fathers with BD. Fathers do not undergo the same biological changes as mothers during the perinatal period which may partly explain the different patterns observed in the type and timings of PMEs between fathers and mothers with BD. Prospective longitudinal studies are needed to explore specific potential risk factors.

The increasing availability of biobanks is changing the way individuals are identified for genomic research. This study assesses the validity of a self-reported clinical diagnosis of schizophrenia. The study included 1744 clinically-ascertained participants with schizophrenia or schizoaffective disorder depressed-type (SA-D) diagnosed by self-report and/or research interview and 1453 UK Biobank participants with self-reported and/or medical record diagnosis of schizophrenia or SA-D. Unaffected controls included a total of 501,837 participants. We assessed the positive predictive values (PPV) of self-reported clinical diagnoses against research interview and medical record diagnoses. Polygenic risk scores (PRS) and phenotypes relating to demographics, education and employment were compared across diagnostic groups. The variance explained (r2) in schizophrenia PRS for each diagnostic group was compared to samples in the Psychiatric Genomics Consortium (PGC). In the clinically-ascertained participants, the PPV of self-reported schizophrenia for a research diagnosis of schizophrenia was 0.70, which increased to 0.81 after expanding the research diagnosis to schizophrenia or SA-D. In UK Biobank, the PPV of self-reported schizophrenia for a medical record diagnosis was 0.74. Compared to participants who self-reported, participants with a clinically-ascertained research diagnosis were younger and more likely to have a high school qualification. Participants with a medical record diagnosis in UK Biobank were less likely to be employed or have a high school qualification than those who self-reported. Schizophrenia PRS did not differ between participants that had a diagnosis from self-report, research diagnosis or medical records. Polygenic liability r2, for all diagnosis definitions, fell within the distribution of PGC schizophrenia cohorts. Self-reported measures of schizophrenia are justified in genomic research to maximise sample size and reduce the burden of in-depth interviews on participants, although within sample validation of diagnoses is recommended.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation. Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

BACKGROUND:Previous studies have shown that genes in brain development pathways may have important roles in affecting risk of suicidal behaviors, with our previous meta-analysis supporting a role of the brain-derived neurotrophic factor (BDNF) gene. NTRK2 is a gene that encodes the neurotrophic receptor tyrosine kinase 2, which is a receptor for BDNF. In the current study, we aim to examine the potential association between NTRK2 single nucleotide polymorphism (SNPs) and suicidal ideation/behaviors. METHODS:We first conducted a literature search using keywords like 'NTRK2', 'TRKB', and 'suicid*' to identify papers on NTRK2 SNPs and suicidal ideation/behaviors. In addition, we have individual-level genotype data for all the identified SNPs in literature search. We used the R meta package to perform meta-analyses on both the genotype count and the allele count data. Moreover, we performed meta-analyses on specific haplotypes within each haplotype block. MAIN RESULTS:Following our literature search and meta-analyses on 20 NTRK2 SNPs across up to 8467 samples, we found three SNPs, rs10868235 [N = 5,318, odds ratio (OR) = 1.34, P = 0.02], rs1867283 (N = 5,134, OR = 0.73, P = 0.04), and rs1147198 (N = 5,132, OR = 1.36, P = 0.03) to be nominally associated with suicidal attempts. Those three findings, however, did not survive multiple-testing corrections. Also, none of the haplotype blocks showed significant involvement in suicidality. CONCLUSION:Our results suggest that the NTRK2 gene may not have a major role in suicidality. Future efforts, however, should explore gene-gene interaction and pathway analyses.

The premenstrual phase of the menstrual cycle, childbirth and perimenopause often coincide with a worsening of mood symptoms in women with bipolar disorder (BD). To date, findings from the limited number of studies investigating associations between these events among women with BD have been inconsistent. This study aimed to investigate associations between episodes in relation to the perimenopause and (i) premenstrual symptoms and (ii) postpartum mood episodes in a large sample of postmenopausal women with BD. Among 567 postmenopausal women with BD, recruited as part of the UK Bipolar Disorder Research Network, relationships between reproductive event-associated mood symptoms/episodes were examined. Multivariate binary analyses were carried out to identify if history of premenstrual symptoms and/or postpartum episodes predicted the occurrence of mood episodes in relation to the perimenopause, controlling for potential confounders including number of mood episodes per illness year. History of premenstrual symptoms was associated with experiencing any type of mood episode, and depression specifically, during the perimenopause (OR 6.189, p < 0.001 and OR 2.709, p = 0.019 respectively). History of postpartum depression within 6 weeks of delivery was associated with depressive episodes during the perimenopause (OR 2.635, p = 0.027). Postpartum mania was not a significant predictor. Our findings suggest that women with BD with a history of premenstrual symptoms and postpartum depression are potentially at increased risk of experiencing episodes of depression in relation to the perimenopause. There are clinical and self-management implications in identifying a subgroup of women with BD who may be particularly vulnerable to episodes of mood disturbance during reproductive events. Relationships between reproductive events investigated among 567 postmenopausal women with bipolar disorder. History of premenstrual symptoms and postpartum depression was associated with episodes of depression during the perimenopause. No significant relationships were identified with (hypo)mania in relation to the perimenopause. A subgroup of women with bipolar disorder may be particularly vulnerable to episodes of mood disturbance during reproductive events.

Background: Despite cross-sectional population and clinical studies finding individuals with existing mood disorders being adversely impacted by the COVID-19 pandemic, longitudinal studies have not shown a worsening of psychiatric symptoms. In response to these findings, we explored opportunities to engage in positive activities during the pandemic from the perspectives of individuals with mood disorders.Methods: A bespoke survey, containing closed and open questions, was sent to participants with mood disorders who were part of the UK Bipolar Disorder Research Network (BDRN). Questions related to experiences of positive impacts of the pandemic, levels of engagement in positive activities and coping strategies.Results: Response rate was 46.4 % (N = 1688). 61.9 % reported positive life changes during the pandemic, with slower pace of life reported most frequently (52.8 %). 47.3 % reported no adverse impact of the pandemic on implementing their usual coping strategies. Activities that respondents most commonly reported the same or greater level of engagement in compared to before the pandemic were avoiding known mood triggers (82.3 %), relaxation techniques (78.8 %) and the ability to maintain set routines (69.4 %). Limitations: Responder bias may be present and experiences during the pandemic are likely to differ among other clinical and research mood disorders cohorts.Conclusions: Our findings may help to explain why longitudinal studies have not found a worsening of mental health symptoms during the COVID-19 pandemic. Identifying potential facilitators to maintaining mental health have wider applicability, and may help to inform future evidence-based psychoeducation and self-management programmes for mood disorders.

Detailed microstructural characterisation of phases present in a next generation polycrystalline Ni based superalloy after thermal exposure at 900 degrees C was carried out, focusing on carbides and borides. Metastable M5B3 precipitated after 32 h had a stoichiometry of (Cr0.7Mo0.2W0.1)5B3 with substitutions with Ni, Co, Nb and Ta. Fine M23C6 (a = 10.62 angstrom) was overgrown by metastable M5B3, as shown by rigorous TEM-SAD pattern investigation. The borides were eventually dominated by Mo rich M3B2, at the apparent expense of MC. Decomposition of MC was confirmed; it transformed sequentially to gamma and then gamma". The primary driving force for the MC decomposition was attributed to gamma" precipitation, increasing its fraction to the thermodynamic equilibrium at 900 degrees C.

OBJECTIVE:Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS:A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS:Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS:Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.