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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.
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INTRODUCTION: Continuity and coordination-of-care for childhood cancer survivors with multiple chronic conditions are understudied but critical for appropriate follow-up care. METHODS: From April through June 2022, 800 Childhood Cancer Survivor Study participants with two or more chronic conditions (one or more severe/life-threatening/disabling) were emailed the "Patient Perceived Continuity-of-Care from Multiple Clinicians" survey. The survey asked about survivors' main (takes care of most health care) and coordinating (ensures follow-up) provider, produced three care-coordination summary scores (main provider, across multiple providers, patient-provider partnership), and included six discontinuity indicators (e.g., having to organize own care). Discontinuity (yes/no) was defined as poor care on one or more discontinuity item. Chi-square tests assessed associations between discontinuity and sociodemographics. Modified Poisson regression models estimated prevalence ratios (PRs) for discontinuity risk associated with the specialty and number of years seeing the main and coordinating provider, and PRs associated with better scores on the three care-coordination summary measures. Inverse probability weights adjusted for survey non-participation. RESULTS: A total of 377 (47%) survivors responded (mean age 48 years, 68% female, 89% non-Hispanic White, 78% privately insured, 74% ≥college graduate); 147/373 (39%) reported discontinuity. Younger survivors were more likely to report discontinuity (chi-square p = .02). Seeing the main provider ≤3 years was associated with more prevalent discontinuity (PR; 95%CI) (1.17; 1.02-1.34 vs ≥ 10 years). Cancer specialist main providers were associated with less prevalent discontinuity (0.81; 0.66-0.99 vs. primary care). Better scores on all three care-coordination summary measures were associated with less prevalent discontinuity: main provider (0.73; 0.64-0.83), across multiple providers (0.81; 0.78-0.83), patient-provider partnership (0.85; 0.80-0.89). CONCLUSIONS: Care discontinuity among childhood cancer survivors is prevalent and requires intervention.
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Until recently, most syringe services programs (SSPs) in the United States operated in metropolitan areas. This study explores how SSP implementers at rural health departments in Kentucky secured support for SSP operations. In late 2020, we conducted in-depth, semi-structured interviews with 18 people involved with rural SSP implementation in Kentucky. Participants were asked to reflect on their experiences building support for SSP operations among rural health department staff and community members. Participants reported that attitudes and beliefs about SSP implementation among rural health department staff shifted quickly following engagement in educational activities and interaction with SSP clients. Participants explained that successful SSP implementation at rural health departments required sustained educational activities among community members and authorizing authorities. Future work should explore how rural communities may advocate for low-threshold and evidence-based policies that support the provision of harm reduction services.
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BACKGROUND: Over 8 million children with disabilities live in Africa and are candidates for augmentative and alternative communication (AAC), yet formal training for team members, such as speech-language therapists and special education teachers, is extremely limited. Only one university on the continent provides postgraduate degrees in AAC, and other institutions provide only short modules at an undergraduate level. The need for an introductory training course on AAC that is accessible by university students continent-wide was identified. An online programme, namely an intelligent tutoring system (ITS), was identified as a possible option to facilitate interactive learning without the need for synchronous teaching. The use of an ITS is shown to be effective in developing knowledge and clinical reasoning in the health and rehabilitation fields. However, it has not yet been applied to student teaching in the field of AAC. AIM: To determine both the feasibility of an ITS to implement an AAC curriculum for students in four African countries, and the usability and effectiveness of such a system as a mechanism for learning about AAC. METHOD & PROCEDURES: The study included two components: the development of a valid AAC curriculum; and using the ITS to test the effectiveness of implementation in a pre- and post-test design with 98 speech-language therapy and special education students from five universities. OUTCOMES & RESULTS: Statistically significant differences were obtained between pre- and post-test assessments. Students perceived the learning experience as practical, with rich content. CONCLUSIONS & IMPLICATIONS: The findings suggest that the ITS-based AAC curriculum was positively perceived by the students and potentially offers an effective means of providing supplementary AAC training to students, although modifications to the system are still required. WHAT THIS PAPER ADDS: What is already known on the subject Professionals typically lack formal training in AAC. In Africa, this presents a serious challenge as there are over 8 million children who are candidates for AAC. A need for an introductory training course on AAC, which can be accessed by university students continent-wide, was identified. What this paper adds to existing knowledge An AAC curriculum was developed and integrated into an ITS, an online programme allowing interactive learning through asynchronous teaching. Students from four African countries completed the AAC ITS curriculum. The curriculum was positively received by the students and statistically significant changes in knowledge were identified. What are the practical and clinical implications of this work? This feasibility study shows that the use of an ITS is an effective means of providing AAC training to university students in these African countries. The results provide a valuable contribution toward ensuring the equitable distribution of AAC training opportunities in the African context. This will have a significant positive impact on those who are candidates for AAC.
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A qualitative study was conducted using semi-structured interviews leaders in community-based organizations, health care, and local public health to understand organizational perspectives of collaboration for health equity and identify opportunities to improve collaboration. Twelve leaders were interviewed from March through May 2023 in Kent County, Michigan. All leaders saw collaboration as valuable for advancing health equity. Key themes that affected collaboration and could be a facilitator or barrier to advancing health equity in the community were inclusion, power, relationships, resources, and organizational traits. Leaders articulated the following factors as those that support collaboration for health equity: authentic inclusion, shared decision-making, taking time to foster trusting relationships, adequate resources to support the infrastructure needed for collaborations, organizational flexibility, and individual commitment. Building partnerships with these facilitators in mind may result in more robust, sustainable, and resilient collaboratives.
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Helminths can adapt to environmental conditions in the host, utilising anaerobic processes like fermentation and malate dismutation to produce energy from carbohydrate. Although targeting carbohydrate metabolism is an established therapeutic strategy to combat helminth infection, questions remain over the metabolic pathways they employ as adults to survive and evade host immunity. Helminths also use amino acid, polyunsaturated fatty acid (PUFA), and cholesterol metabolism, a possible strategy favouring the production of immunomodulatory compounds that may influence survival in the host. Here, we discuss the significance of these differing metabolic pathways and whether targeting of helminth metabolic pathways may allow for the development of novel anthelmintics.
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Helmintiasis , Helmintos , Interacciones Huésped-Parásitos , Animales , Helmintos/inmunología , Helmintos/fisiología , Interacciones Huésped-Parásitos/inmunología , Interacciones Huésped-Parásitos/fisiología , Helmintiasis/inmunología , Helmintiasis/parasitología , Humanos , Antihelmínticos/uso terapéutico , Antihelmínticos/farmacologíaRESUMEN
A benefit-risk assessment of NVX-CoV2373, a vaccine to prevent COVID-19, was conducted to determine if the benefits of vaccination outweigh the risks of myocarditis/pericarditis. This analysis used data on myocarditis/pericarditis cases observed in the NVX-CoV2373 clinical studies, real-world data of mRNA COVID vaccine effectiveness against predominant SARS-CoV-2 strains in early 2023, and recent COVID-19 burden of disease data from the United States. The benefits of NVX-CoV2373 vaccination were estimated as the number of COVID-19 cases, hospitalizations, and deaths prevented. The risks of myocarditis/pericarditis cases and related hospitalizations and deaths occurring within 7 days of vaccination were also estimated. In our analysis, vaccination with NVX-CoV2373, per 100,000 vaccinated, resulted in an estimated 1805 COVID-19 cases prevented compared with an estimated 5.3 excess myocarditis/pericarditis cases. The number of COVID-19 hospitalizations and deaths prevented were also greater than vaccine-associated myocarditis/pericarditis hospitalizations and deaths. Our analysis indicates a positive benefit-risk balance for NVX-CoV2373.
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COVID-19 , Miocarditis , Pericarditis , Humanos , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , SARS-CoV-2 , Vacunación , Vacunas de ARNm , Medición de RiesgoRESUMEN
Adenomyoepithelioma (AME) is a rare, usually benign breast neoplasm with low potential for malignant transformation. Imaging features are nonspecific and overlap with other benign and malignant breast lesions. On mammography, AME most often presents as a mass, usually oval in shape, with variable reported margins. Less commonly, AME can present mammographically as an asymmetry or can be mammographically occult. Associated calcifications are uncommon. On US, AME is usually seen as a hypoechoic oval mass, but it can also manifest as a complex cystic and solid mass. On US, the majority of AME have noncircumscribed margins (indistinct, angular, or microlobulated). Internal vascularity is usually present, and posterior enhancement can be seen. Although there is limited literature on MRI features, the most frequent finding is an irregular mass with washout kinetics; T2 hyperintensity can be observed. These nonspecific and often suspicious imaging features usually merit biopsy. On histologic analysis, AME is characterized by a biphasic proliferation of myoepithelial and epithelial cells. Pathologic diagnosis can be difficult due to the variety of histologic features of AME and heterogeneity in these tumors, especially when sampling is limited, such as in core needle biopsies. Wide local surgical excision of AME is recommended due to potential for recurrence and malignant transformation.
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Adenomioepitelioma , Neoplasias de la Mama , Humanos , Femenino , Adenomioepitelioma/diagnóstico por imagen , Mama/patología , Neoplasias de la Mama/diagnóstico por imagen , Mamografía , BiopsiaRESUMEN
There is increased reliance on newly licensed nurses to fill open healthcare positions. Nurse residency programs (NRPs) provide the training, mentorship, and support newly licensed nurses require to successfully transition to professional practice. Research suggests that NRPs improve nurse retention, clinical outcomes, and organizational outcomes. Sufficient NRP full-time equivalents are needed to ensure adequate support and program management. This article describes how a Colorado hospital system secured additional NRP Coordinator full-time equivalent using a six-step process.
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Internado no Médico , Humanos , Colorado , Desarrollo de Personal , MentoresRESUMEN
The Transtheoretical Model of Change identifies key stages in behavior change, including a maintenance stage occurring when a behavior has been upheld for at least 6 months. Health and wellness coaching has demonstrated support for health behavior change, but maintenance of gains has received little attention. Our rapid systematic literature review characterizes both the research exploring sustained gains with health and wellness coaching and what is known about sustained gains after the completion of a health and wellness coaching engagement. Guided by The Cochrane Rapid Reviews Methods Group "Interim Guidance," we drew 231 studies from the 2018 and 2020 Sforzo et al "Compendium of the health and wellness coaching literature," and "Addendum " appendices. Initial screening and coding for inclusion and exclusion criteria yielded 28 studies for data extraction. We examined studies across outcome categories (physiological, behavioral, psychological, and health risk assessment) to determine whether outcome measures were: not sustained; partially sustained; fully sustained; or improved from immediate post-intervention to a later follow-up period. Twenty-five of the 28 studies reviewed demonstrated partially, or fully, sustained or improved outcomes in one or more variables studied, with sustained gains demonstrated across outcome categories, strengthening confidence in HWC as a facilitator of lasting change.
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BACKGROUND: Pre-diabetes affects one-third of US adults and increases the risk of type 2 diabetes. Effective evidence-based interventions, such as the Diabetes Prevention Program, are available, but a gap remains in effectively translating and increasing uptake of these interventions into routine care. METHODS: We applied the Translating Research into Practice (TRiP) framework to guide three phases of intervention design and development for diabetes prevention: (1) summarise the evidence, (2) identify local barriers to implementation and (3) measure performance. In phase 1, we conducted a retrospective cohort analysis of linked electronic health record claims data to evaluate current practices in the management of pre-diabetes. In phase 2, we conducted in-depth interviews of 16 primary care physicians, 7 payor leaders and 31 patients to elicit common barriers and facilitators for diabetes prevention. In phase 3, using findings from phases 1 and 2, we developed the core elements of the intervention and performance measures to evaluate intervention uptake. RESULTS: In phase 1 (retrospective cohort analysis), we found few patients with pre-diabetes received diabetes prevention interventions. In phase 2 (stakeholder engagement), we identified common barriers to include a lack of knowledge about pre-diabetes among patients and about the Diabetes Prevention Program among clinicians. In phase 3 (intervention development), we developed the START Diabetes Prevention Clinical Pathway as a systematic change package to address barriers and facilitators identified in phases 1 and 2, performance measures and a toolkit of resources to support the intervention components. CONCLUSIONS: The TRiP framework supported the identification of evidence-based care practices for pre-diabetes and the development of a well-fitted, actionable intervention and implementation plan designed to increase treatment uptake for pre-diabetes in primary care settings. Our change package can be adapted and used by other health systems or clinics to target prevention of diabetes or other related chronic conditions.
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Diabetes Mellitus Tipo 2 , Atención Primaria de Salud , Investigación Biomédica Traslacional , Humanos , Atención Primaria de Salud/estadística & datos numéricos , Diabetes Mellitus Tipo 2/prevención & control , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Investigación Biomédica Traslacional/métodos , Adulto , Estado Prediabético/terapia , Investigación Cualitativa , AncianoRESUMEN
BACKGROUND: Health advances due to developments in genomic medicine are unequally experienced in the USA; racial differences in the uptake of genetic testing are one factor in this disparity. In collaboration with Black patients and diverse health care providers, we are developing a patient-centered video intervention to increase cancer genetic testing among eligible Black Americans. The objective of the pilot work is to explore the acceptability of and support for the intervention and key content components. METHODS: In order to create a patient-centered video intervention prototype, we conducted a targeted, secondary analysis of 47 coded transcripts from video-taped qualitative interviews with people with a known genetic or inherited cancer risk. The review focused on decision-making, testing experiences, and perceived value of genetic testing. We subsequently generated a 15-min video montage of content from 9 diverse (age, gender, race) participants. We used the prototype video as prompt material for semi-structured interviews with 10 Black patients who had undergone genetic testing in the last 2 years and 10 racially diverse providers (genetic counselors, a nurse, and medical oncologists) who provide management recommendations for high-risk patients. Interviews sought to understand the acceptability of a video intervention to enhance informed decision-making by Black patients and key elements for intervention efficacy. RESULTS: Study participants were generally positive about the prototype video and provided guidance for intervention development. Interviewed patients prioritized perceived authenticity and relatability of video participants. The presentation of patients' perspectives on testing, their experiences of testing, and the benefits of having test results were all seen as useful. The benefits of testing for self and family were identified as important considerations. Privacy concerns and science skepticism were identified as germane issues, with guidance to present barriers to testing alongside possible solutions. The inclusion of clinicians was seen as potentially useful but with caution that clinicians are not universally trusted. CONCLUSIONS: Study findings provided critical input for the creation of a professionally produced, tailored intervention video for a randomized clinical trial with Black Americans to evaluate the influence on uptake of genetic testing. The interviews suggest the acceptability and potential utility of an authentic, realistic, and tailored, patient-centered video intervention to increase consideration and uptake of genetic testing.
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BACKGROUND Hereditary breast cancer arising in BRCA1-deficient patients is commonly diagnosed as invasive carcinoma of no special type (NST) with medullary features, while invasive lobular carcinoma (ILC) appears to be significantly under-represented in BRCA1 mutation carriers. We report a case of pleomorphic ILC arising in a 28-year-old woman harboring a germline BRCA1 c.3756_3759delGTCT p.(Ser1253Argfs*10) pathogenic variant. CASE REPORT A nulliparous 28-year-old woman with a family history of BRCA1 mutation presented to the symptomatic breast clinic with a several-week history of a left 80-mm breast lump. Core biopsy established a diagnosis of a poorly differentiated triple-negative breast cancer (TNBC) of pleomorphic lobular phenotype. Her clinical diagnosis was cT3, N0, M0, cStageIIB. The MDT recommended CT staging, MRI breast imaging and neoadjuvant chemotherapy (NACT). PET CT imaging showed no evidence of distant metastatic disease. The patient had a good radiological response to NACT with a FEC-T carboplatin regimen. Post-NACT imaging showed a residual cystic mass and the patient underwent a mastectomy and sentinel lymph node biopsy with plans for a delayed latissimus dorsi reconstruction following her adjuvant radiotherapy treatment. A complete pathological response was subsequently demonstrated without any evidence of metastatic disease. CONCLUSIONS This case is the first report of pleomorphic ILC with a triple-negative receptor status and a complete pathological response in a BRCA1 mutation carrier. Our study expands the heterogeneous spectrum of TNBC and contributes to a better understanding of the molecular genetic landscape that characterizes invasive pleomorphic lobular neoplasia.
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Carcinoma Lobular , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/terapia , Adulto , Carcinoma Lobular/genética , Carcinoma Lobular/patología , Carcinoma Lobular/terapia , Proteína BRCA1/genética , Mutación de Línea GerminalRESUMEN
Eastern equine encephalitis virus (EEEV) is the most virulent alphavirus that infects humans, and many survivors develop neurological sequelae, including paralysis and intellectual disability. Alphavirus spike proteins comprise trimers of heterodimers of glycoproteins E2 and E1 that mediate binding to cellular receptors and fusion of virus and host cell membranes during entry. We recently identified very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as cellular receptors for EEEV and a distantly related alphavirus, Semliki Forest virus (SFV). Here, we use single-particle cryo-electron microscopy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR ligand-binding domain and found that EEEV and SFV interact with the same cellular receptor through divergent binding modes. Our studies suggest that the ability of LDLR-related proteins to interact with viral spike proteins through very small footprints with flexible binding modes results in a low evolutionary barrier to the acquisition of LDLR-related proteins as cellular receptors for diverse sets of viruses.
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Microscopía por Crioelectrón , Virus de la Encefalitis Equina del Este , Receptores de LDL , Receptores de LDL/metabolismo , Receptores de LDL/química , Virus de la Encefalitis Equina del Este/metabolismo , Virus de la Encefalitis Equina del Este/ultraestructura , Humanos , Animales , Virus de los Bosques Semliki/metabolismo , Unión Proteica , Receptores Virales/metabolismo , Receptores Virales/química , Proteínas del Envoltorio Viral/metabolismo , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/ultraestructura , Modelos MolecularesRESUMEN
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.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Herencia Multifactorial , Sistema de Registros , Ausencia por Enfermedad , Humanos , Trastorno Bipolar/genética , Trastorno Bipolar/epidemiología , Masculino , Femenino , Herencia Multifactorial/genética , Adulto , Suecia/epidemiología , Ausencia por Enfermedad/estadística & datos numéricos , Persona de Mediana Edad , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/epidemiología , Hospitalización/estadística & datos numéricos , Escolaridad , Desempleo/estadística & datos numéricos , Esquizofrenia/genética , Esquizofrenia/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Estudios Longitudinales , Estudios de Casos y ControlesRESUMEN
Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.
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Diabetes Mellitus Tipo 2 , Células Madre Pluripotentes Inducidas , Hepatopatías , Proteínas del Tejido Nervioso , Adulto , Humanos , Proteínas Adaptadoras Transductoras de Señales/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Obesidad/complicaciones , Obesidad/genética , ProteómicaRESUMEN
Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.