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Functional Lyocell fibers gain interest in garments and technical textiles, especially when equipped with inherently bioactive features. In this study, Lyocell fibers are modified with an ion exchange resin and subsequently loaded with copper (Cu) ions. The modified Lyocell process enables high amounts of the resin additive (>10%) through intensive dispersion and subsequently, high uptake of 2.7% Cu throughout the whole cross-section of the fiber. Fixation by Na2CO3 increases the washing and dyeing resistance considerably. Cu content after dyeing compared to the original fiber value amounts to approx. 65% for reactive, 75% for direct, and 77% for HT dyeing, respectively. Even after 50 household washes, a recovery of 43% for reactive, 47% for direct and 26% for HT dyeing is proved. XRD measurements reveal ionic bonding of Cu fixation inside the cellulose/ion exchange resin composite. A combination of the fixation process with a change in Cu valence state by glucose/NaOH leads to the formation of Cu2O crystallites, which is proved by XRD. Cu fiber shows a strong antibacterial effect against Staphylococcus aureus and Klebsiella pneumonia bacteria, even after 50 household washing cycles of both >5 log CFU. In nonwoven blends with a share of only 6% Cu fiber, a strong antimicrobial (CFU > log 5) and full antiviral effectiveness (>log 4) was received even after 50 washing cycles. Time-dependent measurements already show strong antiviral behavior after 30 s. Further, the fibers show an increased die off of the fungal isolate Candida auris with CFU log 4.4, and nonwovens made from 6% Cu fiber share a CFU log of 1.7. Findings of the study predestines the fiber for advanced textile processing and applications in areas with high germ loads. [ABSTRACT FROM AUTHOR]

Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function, and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 mM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analysis of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared with effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time to peak under all conditions (maximally two- to threefold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration dependency with maximal effects at 1θmM. Relaxation time tended to fall under auxotonic and strongly increased under isometric conditions, again with biphasic concentration dependency. Diastolic tension concentration dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies. [ABSTRACT FROM AUTHOR]

Introduction Lithium remains the best-established longterm treatment for bipolar disorder because of its efficacy in maintaining periods of remission and reducing the risk of suicide. Not all patients successfully respond to lithium treatment, and the individual response, including the occurrence of side effects, is highly variable and not easy to predict. The genetic basis of lithium response is supported by the fact that the response clusters in families. Likewise, recent high-throughput genomic analyses have shed light on its genetic architecture. Methods This nonsystematic review summarizes the main results obtained in genetic association studies using lithium response as target trait. Results These studies suggest that several genetic loci might modulate the way a patient responds to lithium maintenance treatment. Further studies to fully characterize the genetic architecture of lithium response are warranted. Discussion The identification of genetic factors associated with lithium response will be important for (1) better understanding of lithium's mode of action and (2) development of a predictive model for optimization of long-term treatment of bipolar disorder. [ABSTRACT FROM AUTHOR]

The etiology and clinical course of bipolar disorder are considered to be determined by genetic and environmental factors. Although the kindling hypothesis emphasizes the impact of environmental factors on initial onset, their connection to the outcome and clinical course have been poorly established. Hence, there have been numerous research efforts to investigate the impact of environmental factors on the clinical course of illness. Our aim is to outline recent research on the impact of environmental determinants on the clinical course of bipolar disorder. We carried out a computer-aided search to find publications on an association between environmental factors, life events, and the clinical course of bipolar disorder. Publications in the reference lists of suitable papers have also been taken into consideration. We performed a narrative overview on all eligible publications. The available body of data supports an association between environmental factors and the clinical course of bipolar disorder. These factors comprise prenatal, early-life, and entire lifespan aspects. Given varying sample sizes and several methodological limitations, the reported quality and extent of the association between environmental factors and the clinical course of bipolar disorder should be interpreted with utmost caution. Systematic longitudinal long-term follow-up trials are needed to obtain a clearer and more robust picture. [ABSTRACT FROM AUTHOR]

The article investigates developments in the field of psychiatric genetics as of 2018. Topics discussed include the significance of the completion of the Human Genome Project in 2000 on the study of the genetic aspects of psychiatric illness, the role that data sharing played in the success of genome-wide association studies (GWAS) and the need for the psychiatric genetics field to include underrepresented populations in the studies to enable the discipline to progress.

• Clinical response to lithium treatment in bipolar disorder is heterogeneous. • Genetics may explain such a heterogeneity. • Genomic approaches have already identified suggestive regions in our DNA associated with lithium response. • Recent advances in cellular models, high throughput analysis, and statistical methodologies may catalyze advances in this field. Lithium is an effective mood stabilizer in bipolar disorder (BD). There is, however, high variability in treatment response to lithium and only 20–30% of individuals with BD are excellent responders. This subgroup has been shown to have specific phenotypic characteristics, and family studies have implicated genetics as an important factor. However, candidate gene studies did not find evidence for major effect genes. Genome-wide association studies (GWAS) have emphasized that lithium response is a polygenic trait. GWAS based on larger sample sizes and non-European ancestries are likely to shed light on the genomic architecture of this trait. Furthermore, induced pluripotent stem cells, transcriptomics, epigenetics, the integration of multiple omics data, and their combination with advanced machine learning techniques hold promise for the understanding of the complex biological underpinnings of lithium treatment response. [ABSTRACT FROM AUTHOR]

Significant cognitive dysfunction has been recognized as an important state and trait feature of bipolar disorder. In this article, longitudinal studies comparing cognitive performance in bipolar disorder patients and healthy controls are reviewed. In contrast to cross-sectional reports, current longitudinal research findings do not support a progressive cognitive decline over time. However, a higher within-person instability in cognitive performance was found relative to controls. The need for larger samples remains, as well as for longer and more frequent observations. [ABSTRACT FROM AUTHOR]

Mood disorders, including bipolar disorder and depression, are relatively common human diseases for which pharmacological treatment options are often not optimal. Among existing pharmacological agents and mood stabilizers used for the treatment of mood disorders, lithium has a unique clinical profile. Lithium has efficacy in the treatment of bipolar disorder generally, and in particular mania, while also being useful in the adjunct treatment of refractory depression. In addition to antimanic and adjunct antidepressant efficacy, lithium is also proven effective in the reduction of suicide and suicidal behaviors. However, only a subset of patients manifests beneficial responses to lithium therapy and the underlying genetic factors of response are not exactly known. Here we discuss preclinical research suggesting mechanisms likely to underlie lithium's therapeutic actions including direct targets inositol monophosphatase and glycogen synthase kinase-3 (GSK-3) among others, as well as indirect actions including modulation of neurotrophic and neurotransmitter systems and circadian function. We follow with a discussion of current knowledge related to the pharmacogenetic underpinnings of effective lithium therapy in patients within this context. Progress in elucidation of genetic factors that may be involved in human response to lithium pharmacology has been slow, and there is still limited conclusive evidence for the role of a particular genetic factor. However, the development of new approaches such as genome-wide association studies (GWAS), and increased use of genetic testing and improved identification of mood disorder patients sub-groups will lead to improved elucidation of relevant genetic factors in the future. [ABSTRACT FROM AUTHOR]

Current approaches for reducing IT's environmental impact typically are generic and rarely take into account services' actual functionality. To develop more powerful, service-specific strategies for reducing IT's carbon footprint, we need more complete and widely understandable specifications that describe exactly a service's functionality, the level of quality it achieves, and its environmental consequences. Such green specifications will allow more stakeholders involved in the delivery and consumption of IT services to understand their detailed functionality and the tradeoffs between quality of service and environmental impact entailed in their use. This will not only increase the opportunities for optimizing the delivery of services but also provide the foundation for new business models that encourage users to make greener consumption choices. [ABSTRACT FROM PUBLISHER]

Objectives. Genome-wide association studies (GWAS) in complex phenotypes, including psychiatric disorders, have yielded many replicated findings, yet individual markers account for only a small fraction of the inherited differences in risk. We tested the performance of polygenic models in discriminating between cases and healthy controls and among cases with distinct psychiatric diagnoses. Methods. GWAS results in bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SZ), and Parkinson's disease (PD) were used to assign weights to individual alleles, based on odds ratios. These weights were used to calculate allele scores for individual cases and controls in independent samples, summing across many single nucleotide polymorphisms (SNPs). How well allele scores discriminated between cases and controls and between cases with different disorders was tested by logistic regression. Results. Large sets of SNPs were needed to achieve even modest discrimination between cases and controls. The most informative SNPs were overlapping in BD, SZ, and MDD, with correlated effect sizes. Little or no overlap was seen between allele scores for psychiatric disorders and those for PD. Conclusions. BD, SZ, and MDD all share a similar polygenic component, but the polygenic models tested lack discriminative accuracy and are unlikely to be useful for clinical diagnosis. [ABSTRACT FROM AUTHOR]

The heme-binding protein SOUL3 of Chlamydomonas reinhardtii is primarily localized in the pigment globule layer of the eyespot, a primitive visual system. SOUL3 is involved in determining the size and position of the eyespot.The flagellated green alga Chlamydomonas reinhardtii has a primitive visual system, the eyespot. It is situated at the cells equator and allows the cell to phototax. In a previous proteomic analysis of the eyespot, the SOUL3 protein was identified among 202 proteins. Here, we investigate the properties and functions of SOUL3. Heterologously expressed SOUL3 is able to bind specifically to hemin. In C. reinhardtii, SOUL3 is expressed at a constant level over the diurnal cycle, but forms protein complexes that differ in size during day and night phases. SOUL3 is primarily localized in the eyespot and it is situated in the pigment globule layer thereof. This is in contrast to the channelrhodopsin photoreceptors, which are localized in the plasma membrane region of the eyespot. Knockdown lines with a significantly reduced SOUL3 level are characterized by mislocalized eyespots, a decreased eyespot size, and alterations in phototactic behavior. Mislocalizations were either anterior or posterior and did not affect association with acetylated microtubules of the daughter four-membered rootlet. Our data suggest that SOUL3 is involved in the organization and placement of the eyespot within the cell. [ABSTRACT FROM PUBLISHER]

The unicellular green alga Chlamydomonas reinhardtii has two flagella and a primitive visual system, the eyespot apparatus, which allows the cell to phototax. About 40 years ago, it was shown that the circadian clock controls its phototactic movement. Since then, several circadian rhythms such as chemotaxis, cell division, UV sensitivity, adherence to glass, or starch metabolism have been characterized. The availability of its entire genome sequence along with homology studies and the analysis of several sub-proteomes render C. reinhardtii as an excellent eukaryotic model organism to study its circadian clock at different levels of organization. Previous studies point to several potential photoreceptors that may be involved in forwarding light information to entrain its clock. However, experimental data are still missing toward this end. In the past years, several components have been functionally characterized that are likely to be part of the oscillatory machinery of C. reinhardtii since alterations in their expression levels or insertional mutagenesis of the genes resulted in defects in phase, period, or amplitude of at least two independent measured rhythms. These include several RHYTHM OF CHLOROPLAST (ROC) proteins, a CONSTANS protein (CrCO) that is involved in parallel in photoperiodic control, as well as the two subunits of the circadian RNA-binding protein CHLAMY1. The latter is also tightly connected to circadian output processes. Several candidates including a significant number of ROCs, CrCO, and CASEIN KINASE1 whose alterations of expression affect the circadian clock have in parallel severe effects on the release of daughter cells, flagellar formation, and/or movement, indicating that these processes are interconnected in C. reinhardtii. The challenging task for the future will be to get insights into the clock network and to find out how the clock-related factors are functionally connected. In this respect, system biology approaches will certainly contribute in the future to improve our understanding of the C. reinhardtii clock machinery. [ABSTRACT FROM AUTHOR]

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: The majority of research into functional psychosis has proceeded under the assumption that schizophrenia and bipolar disorder are distinct entities with separate underlying disease processes and treatments. This view has been increasingly challenged in both clinical and genetic studies. Findings in recent association studies at two specific genes suggest that the occurrence of mood-incongruent psychotic features may indicate a relatively homogeneous subset of the bipolar phenotype. We examined this hypothesis. Methods: Caucasian affected individuals were ascertained from Europe (the United Kingdom, the Republic of Ireland, Germany, Italy and Andalusia). Consensus best-estimate diagnoses were assigned by two independent raters according to all available information. There was no cross-site evaluation of inter-rater reliability. Families multiply affected by bipolar spectrum mood disorder were selected, comprising 383 affected relative pairs. Individuals were considered to be affected if they were diagnosed with DSM-IV bipolar I disorder or schizoaffective disorder, bipolar type. Multipoint, affected relative pair covariate linkage analysis was performed. Results: Significant familiality of incongruent psychosis was observed [intra-class correlation coefficient (ICC) = 0.309; p = 0.001, one-tail]. Covariate linkage analysis provided three regions with genome-wide suggestive evidence for linkage on chromosomes 1q32.3 (LOD = 4.15, expected 0.12 times per genome scan), 7p13 (LOD = 3.32) and 20q13.31 (LOD = 2.98). No region in our analysis met criteria for genome-wide significance. Conclusion: Our results provide molecular support for the hypothesis that genes may exist for specific forms of bipolar illness, dependent on the presence or absence of incongruent psychosis. Our findings suggest that researchers should take account of mood-congruence/incongruence of psychotic features in studies of bipolar disorder. [ABSTRACT FROM AUTHOR]

El trastorno afectivo bipolares una enfermedad hereditaria que se caracteriza por episodios de manía y depresión recurrentes, aunque no se dispone de información sobre el carácter familiar de la recurrencia de los episodios y las características clínicas relacionadas. Los autores analizaron la frecuencia de las recurrencias de los episodios afectivos (número de episodios) y las variables clínicas y demográficas asociadas, en familias en las que al menos tres miembros padecían un trastorno afectivo mayor. Método: Los miembros de 86 familias, identificadas a través de probandos con trastorno afectivo bipolar y dos o más familiares de primer grado con trastorno afectivo mayor, fueron entrevistados y diagnosticados por psiquiatras basándose en todos los datos disponibles. Se analizaron los datos de 407 individuos con trastorno afectivo mayor. La frecuencia de los episodios se calculó como el número de episodios de depresión mayor, manía e hipomanía por año de enfermedad. Resultados: La periodicidad de los episodios se distribuyó de manera homogénea a lo largo de 0,02-20,2 episodios anuales y se relacionó significativamente entre los familiares (r = 0,56, p < 0,004). Una edad de inicio más temprana, el trastorno bipolar II, las alucinaciones o las ideas delirantes, el alcoholismo y las conductas suicidas fueron más frecuentes en el cuartil más alto del número de episodios que en el cuartil más bajo. El sexo femenino y la depresión mayor recurrente fueron más frecuentes en el cuartil más bajo. El trastorno de angustia, el abuso de sustancias y la enfermedad tiroidea no se relacionaron con la periodicidad de los episodios. Los individuos con ciclos rápidos, según el DSM-IV, no difirieron de los demás individuos afectados en la mayoría de las variables analizadas. Conclusiones: La periodicidad de los episodios es una característica altamente hereditaria del trastorno afectivo bipolar, relacionada con diversos indicadores de gravedad, y podría ser útil para definir los subtipos clínicos del trastorno afectivo bipolar con mayor predisposición genética. Estos datos no confirmaron que la ciclación rápida, definida por el DSM-IV, fuera el mejor factor predictivo del carácter hereditario o de gravedad. [ABSTRACT FROM PUBLISHER]

Abstract: Human genetics has now advanced to the stage that technology is no longer the limiting step in mapping genes that contribute to disease. Instead we now must confront the problems inherent in our diagnostic definitions—what geneticists call phenotypes. This challenge is nowhere clearer than in the field of bipolar affective disorder, where genetic methods have given us a tantalizing glimpse at etiology, but where the imprecision and heterogeneity of the phenotype have slowed progress. It is now time to return to the phenotype as a chief focus of genetic investigation. [Copyright &y& Elsevier]

Objective: Bipolar affective disorder is a familial illness characterized by recurrent episodes of mania and depression, but little is known about the familial nature of episode recurrence or its associated clinical features. The authors analyzed the recurrence frequency of affective episodes (episode frequency), along with associated clinical and demographic variables, in families with at least three members with a major affective disorder. Method: Members of 86 families ascertained through probands with bipolar affective disorder who had two or more first-degree relatives with a major affective disorder were interviewed by psychiatrists and assigned an all-sources diagnosis. Data for 407 subjects with a major affective disorder were analyzed. Episode frequency was estimated as the number of episodes of major depression, mania, and hypomania per year of illness. Results: Episode frequency was smoothly distributed over the range of 0.02-20.2 episodes/year. Episode frequency as significantly correlated among relatives (r=0.56, p<0.004). Earlier age at onset, bipolar II disorder, hallucinations or delusions, alcoholism, and suicidal behavior were all more prevalent in the highest than in the lowest quartiles of episode frequency. Female gender and recurrent major depression were more prevalent in the lowest quartile. Panic disorder, substance abuse, and thyroid disease were all unrelated to episode frequency. Subjects with DSM-IV rapid cycling did not differ from other affected subjects for most of the variables tested. Conclusions: Episode frequency is a highly familial trait in bipolar affective disorder, associated with several indicators of severity, and may be useful in defining clinical subtypes of bipolar affective disorder with greater genetic liability. DSM-IV rapid cycling was not supported by these data as the best predictor of familiality or severity. [ABSTRACT FROM AUTHOR]

Background: Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of affective illness. A 44-base-pair insertion/deletion polymorphism in the 5′ regulatory region of the serotonin transporter gene (5-HTTLPR), which influences expression of the serotonin transporter, has been the focus of intensive research since an initial report on an association between 5-HTTLPR and depression-related personality traits. Consistently replicated evidence for an involvement of this polymorphism in the etiology of mood disorders, particularly in major depressive disorder (MDD), remains scant. Methods: We assessed a potential association between 5-HTTLPR and MDD, using the largest reported sample to date (466 patients, 836 control subjects). Individuals were all of German descent. Patients were systematically recruited from consecutive inpatient admissions. Control subjects were drawn from random lists of the local Census Bureau and screened for psychiatric disorders. Results: The short allele of 5-HTTLPR was significantly more frequent in patients than in control subjects (45.5% vs. 39.9%; p = .006; odds ratio = 1.26). Conclusions: These results support an involvement of 5-HTTLPR in the etiology of MDD. They also demonstrate that the detection of small genetic effects requires very large and homogenous samples. [Copyright &y& Elsevier]

Reviewing the history pf psychiatric genetics is a difficult task, since--in contrast to genetic research into most other disorders--it cannot simply be done by chronologically Hiring methodological achievements and major findings. Instead, it necessitates a comprehensive assessment of how the aetiological concept of menial disorders has developed since as early as the world of ancient Greece. Furthermore, it has to touch upon the sensitive issue of the eugenic movement that was closely linked to the study of heredity in mental disorders in the first half of the 20th century and, in Nazi Germany, led to the systematic mass murder of psychiatric patients. Finally, reviewing the scientific dimensions, history of psychiatric genetics is at the same lime a walk through the history of complex genetics in general. In our review, we try to pay tribute to this complexity. We argue that psychiatric genetics has not only propelled our understanding of mental disorders but has significantly benefited genetic research into other complex disorders through the development of methodologically robust approaches (e.g., systematic phenotype characterisation, methods to control for ascertainment biases, age-correction). Given the recent reasons for new optimism, i.e., the identification of susceptibility genes for psychiatric phenotypes, a continued methodologically sound approach is needed more than ever to guarantee robust results. Finally, psychiatric genetic research should never again be performed in an environment void of ethical standards. [ABSTRACT FROM AUTHOR]

Background: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3–22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p.Methods: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed.Results: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p = .006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r = .26; p < .0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p < .0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from .35 to 2.26 on 6p22.2.Conclusions: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia. [Copyright &y& Elsevier]

: BackgroundWe recently reported evidence of linkage of bipolar disorder to chromosome 18q, with a paternal logarithm of odds (LOD) score of 4.67 (p = .004) in a clinically defined subset of families. Like other linkage studies, we had to rely on imprecise genetic maps to establish the marker order. Here, we test for linkage in the same sample with a denser set of markers, now physically ordered according to the draft sequence of the human genome.: MethodsFamilies were ascertained through probands with bipolar I disorder and diagnosed with reliable methods. Genotypes were generated for 12 microsatellite markers within an 11-centimorgan (cM) region of chromosome 18q22. Multipoint affected sib-pair linkage analysis was performed in a set of 16 nuclear families.: ResultsThe additional markers significantly increased the total genetic information extracted from our sample. We also observed an increase in the LOD score (to 5.42, p = .0066) and linkage resolution. The approximate 1-LOD support interval is now 9 male cM.: ConclusionsThe results strengthen our previous findings and further define a region suitable for genetic fine-mapping analysis on chromosome 18q. Our data suggest that a dense set of markers, when physically ordered, can increase the informational value of genetic linkage signals. [Copyright &y& Elsevier]

Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3β pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3β pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response. [ABSTRACT FROM AUTHOR]

Summary Accurate clustering of mixed data, encompassing binary, categorical, and continuous variables, is vital for effective patient stratification in clinical questionnaire analysis. To address this need, we present longmixr, a comprehensive R package providing a robust framework for clustering mixed longitudinal data using finite mixture modeling techniques. By incorporating consensus clustering, longmixr ensures reliable and stable clustering results. Moreover, the package includes a detailed vignette that facilitates cluster exploration and visualization. Availability and implementation The R package is freely available at https://cran.r-project.org/package=longmixr with detailed documentation, including a case vignette, at https://cellmapslab.github.io/longmixr/. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Overall Abstract: b This symposium is dedicated to showcase the current psychiatric genetics, studies on under-represented population outside of the United States and major developed countries. The genetic study has been similarly focused on schizophrenia and autism by GWAS, CNV and de novo mutations. The Chinese schizophrenia and major depression GWAS are two of the biggest psychiatric GWAS published so far.

Highlights from the article: B Abstract: b Over the past years, several GWAS have attempted to identify genetic factors associated with lithium response in bipolar disorder. The ConLiGen consortium was founded in 2008 with the aim to conduct a multicenter genome-wide association study of lithium response using a standardized phenotypic response definition (www.conligen.org). The results of the GWAS, published in 2016, showed a genome-wide significant association of treatment response with a locus on chromosome 21, in a region coding for 2 long noncoding RNAs (lnRNA).

Health is a state of complete physical, mental, and social well‐being and not merely the absence of disease or infirmity. The multifaceted intertwined nature of optimal health, mental health, and well‐being requires operational, sustainable interdisciplinary partnerships in order to improve personal and global well‐being and happiness. The initial step must be the assessment of the nature and magnitude of local problems in the global context. The WHO annual reports may be an adequate departure point as they can demonstrate the global nature of stressful situations and their association with physical and mental stress‐related disorders. Therein, mental health professionals should spearhead change and progress. Attitudes need to be pro‐active and partnerships are essential. Pertinent data should be evaluated by local experts who will determine the needs and how best to face them and achieve solutions. Hopefully, common regional denominators will lead to the formation of Regional Interdisciplinary Collaborative Alliances (RICAs) who will share needed resources and focus particularly on vulnerable populations. The RICAs would be supported by experts and technological facilities located in developed economy centers. The long‐term goal is to turn the concept of pursuit of happiness into a well‐perceived reality. [ABSTRACT FROM AUTHOR]

Undoubtedly, genomic information is getting more and more available via new technologies and becomes part in clinical every-day life. The very personal and foretelling character of genomic information is unique and therefore medical, juridical and ethical implications are widely discussed (Ayuso et al. 2013; Knoppers et al. 2015; Ryan et al. 2017). In addition, there are psychosocial aspects such as self-fulfilling prophecy that might influence an individual´s reaction towards genomic information (Colloca und Finniss 2012; Hagerty et al. 2005). In our study, we surveyed various groups (e.g. patients, experts, and the general population) on their fears, expectations, and their attitudes towards genomic information and their personality traits. Using a 68-item online questionnaire, we asked different stakeholders in Germany about their knowledge of genetics, professional experiences in the genetic context and their personal attitudes, fears, and expectations. We specifically focused on the disclosure and the confrontation with genomic findings. In addition, we measured the Big Five Personality traits (e.g. Neuroticism, Extraversion) with a short version of NEO-FFI (Fruyt et al. 2004). The recruitment started in May 2016 and so far the sample includes 1271 subjects in total, 860 out of which completed the survey. Another focus of our study was to find out whether changes in the information given, as subtle as they might be, lead to divergent decisions. When we asked individuals with a (live-time history of) psychiatric disorder if they would wish to receive genomic information about a psychiatric disorder 31% agreed, whereas only 15% of individuals with no psychiatric disorder agreed. Presenting a scenario in which a person receives the information that he or she is likely to develop Alzheimer's disease, 75% of non-medical participants expected the person to promote healthy behavior after the finding, whereas only 53% of people who studied medicine agreed to that statement. Furthermore, we analyzed if specific personality traits were related to specific attitudes (e.g. neuroticism and openness towards genomic information). Analysis showed a low positive correlation between scoring higher on neuroticism and wanting a physician to have the legal duty to disclose incidental findings in research context (r=.138, p=.000). Our survey sheds light on the diversity of attitudes towards genomic information. For clinical practice, it is crucial to understand that the way how genomic information is presented and communicated to a stakeholder as well as the personality of the individuals themselves (expectations, fears and personality) might impact on the consequences of disclosing genomic information and resulting individual medical decisions. [ABSTRACT FROM AUTHOR]

This presentation will give the audience an overview of current efforts to identify biomarkers of response to lithium treatment in bipolar disorder (BD). First, building on the experience of the Consortium on Lithium Genetics (www.conligen.org), I will underscore how our approach of "friendly data sharing", honoring the invaluable efforts by all researchers involved, clinicians and basic scientists alike, has been pivotal to the success of the ConLiGen GWAS in more than 2,500 individuals, i.e. and how it will shape the next steps. Second, I will present in-depth analyses on a potential link between lithium response and genes involved in circadian rhythms, based on stringent gene-set analyses. Finally, I will talk about latest transcriptomic approaches that might help shed light on lithium's mechanism of action. [ABSTRACT FROM AUTHOR]

One of the primary missions of the ISPG is to spread state-of-the-art research into the genetics of mental illness around the globe. In so doing, we strive to adhere to the highest standards of scientific practice, to learn about regional chances and challenges, and to foster collaborations across continents. To this end, the ISPG has established a standing committee, the Global Diversity Task Force, bringing together researchers from all continents. A major focus of the Task Force's work lies on the empowerment of early career investigators. Furthermore, the Task Force aims at identifying obstacles that impede researchers' access to funding and other resources needed for successful research. In this symposium, we will learn about the latest developments on these "frontiers' from researchers from Latin America, Africa, Eastern Europe, and Asia. [ABSTRACT FROM AUTHOR]

Background: Research on people deprived of liberty raises serious questions, especially concerning behavioral genetic studies. Question: Does including criminally detained patients with mental disorders in genetic studies lead to a gain of new knowledge and can this be ethically and legally justified? Method: Evaluation of existing literature and interdisciplinary reflection. Results: After a review of research ethics and legal norms, we consider the benefits and risks of behavioral genetic research, taking the unique situation of test persons deprived of their liberty into account. The fundamental right to freedom of research also justifies foundational research in forensic psychiatry and psychotherapy. The possible future benefits of improving treatment plans must be weighed against the risks resulting from potential data leaks and inappropriate public reception of research results. Then we analyze possible threats to voluntary and informed consent to study participation in more detail by the ethical concept of vulnerability. Alongside problems with grasping complex issues, above all dependencies and power dynamics in the correctional system play a pivotal role. Recommendations on the ethical and legal inclusion of this study population are given. Conclusion: Including criminally detained study participants can be ethically and legally justified when autonomous consent is supported by specific organizational and legal procedures and measures, for example via a clear professional and organizational separation of correction and research. [ABSTRACT FROM AUTHOR]

Antipsychotic-induced weight gain (AIWG) is a common adverse event in schizophrenia. Genome-wide association studies (GWAS) and polygenic risk scores (PRS) for other diseases or traits are recent approaches to disentangling the genetic architecture of AIWG. 200 patients with schizophrenia treated monotherapeutically with antipsychotics were included in this study. A multiple linear regression analysis with ten-fold crossvalidation was performed to predict the percentage weight change after five weeks of treatment. Independent variables were sex, age, body mass index (BMI) at baseline, medication-associated risk, and PRSs (BMI, schizophrenia, diabetes, and metabolic syndrome). An explorative GWAS analysis was performed on the same subjects and traits. PRSs for BMI (β = 3.78; p = 0.0041), schizophrenia (β = 5.38; p = 0.021) and diabetes type 2 (β = 13.4; p = 0.046) were significantly associated with AIWG. Other significant factors were sex, baseline BMI and medication. Compared to the model without genetic factors, the addition of PRSs for BMI, schizophrenia, and diabetes type 2 increased the goodness of fit by 6.5 %. The GWAS identified the association of three variants (rs10668573, rs10249381 and rs1988834) with AIWG at a genome-wide level of p < 1 · 10−6. Using PRS for schizophrenia, BMI, and diabetes type 2 increased the explained variation of predicted weight gain, compared to a model without PRSs. For more precise results, PRSs derived from other traits (ideally AIWG) should be investigated. Potential risk variants identified in our GWAS need to be further investigated and replicated in independent samples. [ABSTRACT FROM AUTHOR]

Abstract: The Consortium on Lithium Genetics (ConLiGen) is an international collaborative effort that investigates genetic determinants of the response to lithium in bipolar disorder. Here, we summarize our motivation and the current status of ConLiGen's research efforts. While it is known that genetic factors play a major role in the therapeutic effects of lithium, studies into the molecular underpinnings of lithium response have not produced any conclusive evidence so far. This may in part be due to limited sample sizes and varying definitions of response across studies. Since its foundation in 2008, it has been ConLiGen's mission to change that situation. We have now established reliable definitions of response and collected a sample of close to 3000 patients, currently being analyzed at a genome-wide level for genetic determinants of response to lithium. ConLiGen is an ever growing initiative open for researchers interested in understanding lithium's mode of action. [Copyright &y& Elsevier]

Background: Subclinical psychotic experiences (PLEs) are among the frequently reported mental health problems in children/adolescents. PLEs identified in cross sectional studies of children/adolescents are associated with current and future mental health problems. These associations are stronger for PLEs that persist over time. Hence, it could be useful to examine which children/adolescents with PLEs at a first assessment (baseline) are more likely to have PLEs at subsequent assessments.Methods: We conducted a scoping review of studies that examined whether characteristics of children/adolescents (≤18 years) with PLEs at baseline predict whether PLEs are likely to be persistent or remittent at subsequent assessments. We included studies published between January 2002 and December 2017, conducted on general child/adolescent populations of ≥300 individuals, that provided data on PLEs for at least 2 time points, had available follow-up data for ≥50% of those assessed for PLEs at baseline and targeted for follow-up examination, and reported the differences between individuals with PLEs that persisted or remitted during the study period.Results: Six studies met our criteria. Each of them investigated a wide range of baseline characteristics but no predictor of persistence was replicated.Conclusions: Our knowledge about which children/adolescents with PLEs at an initial assessment are likely to have persistent PLEs at subsequent assessments is sparse. A handful of predictors of persistent PLEs have been investigated so far, and none replicated. A better understanding of these predictors would be an important complement to investigations examining the evolution of PLEs and of mental health problems in children/adolescents. [ABSTRACT FROM AUTHOR]

Psychiatric genetics has made tremendous progress over the last two decades. Large-scale collaborative efforts and major developments in molecular biological technologies, in particular genome-wide association studies (GWAS) have helped identify well over a hundred vulnerability genes for schizophrenia at genome - wide and thus robust levels of significance. With an ever increasing sample size for GWAS in bipolar disorder or major depression totaling several tens of thousands of patients and control individuals, the number of identified risk genes for these disorders is expected to rise as well. The polygenic background susceptibility identified by GWAS is complemented by studies interrogating rare genetic variation such as copy number variants (CNVs) or by whole genome sequencing approaches. Large consortia on pharmacogenetics or imaging genetics are adding to our knowledge of the genetic architecture of psychiatric illness. Notwithstanding these scientific successes, the challenges facing the psychiatric genetic community are manifold: Can findings readily be translated from bench to bedside? How to communicate them to physicians, patients, their relatives, and the general public? What are the ethical, legal, and societal implications of genomic research? Following an update on the state-of-the art of psychiatric genetics, this workshop will discuss the aforementioned challenges. A critical appraisal of approaches like the use of polygenic scores or rare genetic variation for predictive purposes will be given. The usefulness of widely marketed direct-to-consumer tests including pharmacogenetic tests will be discussed. Finally, latest studies on people's attitudes towards genetic research in psychiatry and its introduction to clinical settings will be presented. [ABSTRACT FROM AUTHOR]

Over the last few years, extracellular vesicles (EVs) have received increasing attention as potential non-invasive diagnostic and therapeutic biomarkers for various diseases. The interest in EVs is related to their structure and content, as well as to their changing cargo in response to different stimuli. One of the potential areas of use of EVs as biomarkers is the central nervous system (CNS), in particular the brain, because EVs can cross the blood–brain barrier, exist also in peripheral tissues and have a diverse cargo. Thus, they may represent "liquid biopsies" of the CNS that can reflect brain pathophysiology without the need for invasive surgical procedures. Overall, few studies to date have examined EVs in neuropsychiatric disorders, and the present evidence appears to lack reproducibility. This situation might be due to a variety of technical obstacles related to working with EVs, such as the use of different isolation strategies, which results in non-uniform vesicular and molecular outputs. Multi-omics approaches and improvements in the standardization of isolation procedures will allow highly pure EV fractions to be obtained in which the molecular cargo, particularly microRNAs and proteins, can be identified and accurately quantified. Eventually, these advances will enable researchers to decipher disease-relevant molecular signatures of the brain-derived EVs involved in synaptic plasticity, neuronal development, neuro-immune communication, and other related pathways. This narrative review summarizes the findings of studies on EVs in major psychiatric disorders, particularly in the field of biomarkers, and discusses the respective therapeutic potential of EVs. [ABSTRACT FROM AUTHOR]

In clinical practice and in research, there is an ongoing debate on how to return incidental and secondary findings of genetic tests to patients and research participants. Previous investigations have found that most of the people most of the time are in favor of full disclosure of results. Yet, the option to reject disclosure, based on the so-called right not to know, can be valuable especially for some vulnerable subgroups of recipients. In the present study we investigated variations in informational preferences in the context of genetic testing in a large and diverse German sample. This survey examined health care professionals, patients, participants of genetic counseling sessions and members of the general population (N = 518). Survey participants were assessed regarding their openness to learning about findings under various hypothetical scenarios, as well as their attitudes about the doctor-patient-relationship in a disclosure situation and about informational transfer to third parties. While the majority of participants wanted to learn about their findings, the extent of support of disclosure varied with features of the hypothetical diagnostic scenarios (e.g., controllability of disease; abstract vs. concrete scenario description) and demographic characteristics of the subjects. For example, subjects with higher levels of education were more selective with regards to the kind of information they want to receive than those with lower levels of education. We discuss implications of these findings for the debate about the right not to know and for the clinical practice of informed consent procedures. [ABSTRACT FROM AUTHOR]

The article presents a commentary on the medical study "Variant GADL1 and response to lithium therapy in bipolar I disorder" by Chen CH et al. The authors evaluate findings regarding genetic biomarkers which predict the response of patients with bipolar I disorder to therapy with lithium, comment on the single nucleotide polymorphisms (SNPs) variants associated with the encoding of glutamate decarboxylaselike 1 (GADL1), and suggests opinion on further research in the field.

This study aimed to build on the relationship of well-established self-report and behavioral assessments to the latent constructs positive (PVS) and negative valence systems (NVS), cognitive systems (CS), and social processes (SP) of the Research Domain Criteria (RDoC) framework in a large transnosological population which cuts across DSM/ICD-10 disorder criteria categories. One thousand four hundred and thirty one participants (42.1% suffering from anxiety/fear-related, 18.2% from depressive, 7.9% from schizophrenia spectrum, 7.5% from bipolar, 3.4% from autism spectrum, 2.2% from other disorders, 18.4% healthy controls, and 0.2% with no diagnosis specified) recruited in studies within the German research network for mental disorders for the Phenotypic, Diagnostic and Clinical Domain Assessment Network Germany (PD-CAN) were examined with a Mini-RDoC-Assessment including behavioral and self-report measures. The respective data was analyzed with confirmatory factor analysis (CFA) to delineate the underlying latent RDoC-structure. A revised four-factor model reflecting the core domains positive and negative valence systems as well as cognitive systems and social processes showed a good fit across this sample and showed significantly better fit compared to a one factor solution. The connections between the domains PVS, NVS and SP could be substantiated, indicating a universal latent structure spanning across known nosological entities. This study is the first to give an impression on the latent structure and intercorrelations between four core Research Domain Criteria in a transnosological sample. We emphasize the possibility of using already existing and well validated self-report and behavioral measurements to capture aspects of the latent structure informed by the RDoC matrix. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorders (SZ) exhibit considerable phenotypic and genetic overlap. However, the contribution of genetic factors to their shared psychopathological symptom dimensions remains unclear. The present exploratory study investigated genetic contributions to the symptom dimensions "Depression", "Negative syndrome", "Positive formal thought disorder", "Paranoid-hallucinatory syndrome", and "Increased appetite" in a transdiagnostic subset of the German FOR2107 cohort (n = 1042 patients with MDD, BD, or SZ). As replication cohort, a subset of the German/Austrian PsyCourse study (n = 816 patients with MDD, BD, or SZ) was employed. First, the relationship between symptom dimensions and common variants associated with MDD, BD, and SZ was investigated via polygenic risk score (PRS) association analyses, with disorder-specific PRS as predictors and symptom dimensions as outcomes. In the FOR2107 study sample, PRS for BD and SZ were positively associated with "Positive formal thought disorder", the PRS for SZ was positively associated with "Paranoid-hallucinatory syndrome", and the PRS for BD was negatively associated with "Depression". The effects of PRS for SZ were replicated in PsyCourse. No significant associations were observed for the MDD PRS. Second, genome-wide association studies (GWAS) were performed for the five symptom dimensions. No genome-wide significant associations and no replicable suggestive associations (p < 1e−6 in the GWAS) were identified. In summary, our results suggest that, similar to diagnostic categories, transdiagnostic psychiatric symptom dimensions are attributable to polygenic contributions with small effect sizes. Further studies in larger thoroughly phenotyped psychiatric cohorts are required to elucidate the genetic factors that shape psychopathological symptom dimensions. [ABSTRACT FROM AUTHOR]

Neurological soft signs (NSS), minor and subtle neurological abnormalities in sensory integration and motor performance that are not part of a properly defined neurological syndrome, have been consistently observed in patients with schizophrenia. The prevalence estimates of NSS in patients with schizophrenia have been reported to be higher than in healthy subjects. Current evidence suggests that NSS are an integral part of the disease and cannot be fully explained by the exposure to antipsychotic medication, as they are already present in treatmentnaı ve patients. NSS have been associated with cardinal features of the disorder such as cognitive impairment, psychopathological severity, or functional outcome. The increased prevalence of NSS and/or related motor precursors has been described at different stages of development (infancy, childhood, adolescence) in those subjects who later developed schizophrenia. Evidence from family and twin studies indicates that genetic factors play an important role in the emergence of NSS, and some authors have already suggested that such neurological anomalies are suitable endophenotypes for schizophrenia. Some genetic association studies based on a candidate gene approach have already reported the association of genetic variants with the severity of NSS. This non-systematic reviewdescribes the potential relevance of NSS 1) in the understanding of schizophrenia as a neurodevelopmental disorder, 2) as outcome predictors, 3) as biological markers during several stages of development, and 4) as a candidate (endo)phenotype for genetic analyses. Likewise, the possibilities afforded by the advances in high-throughput techniques in genomic analysis are also discussed. [ABSTRACT FROM AUTHOR]

Polygenic Scores (PGS) were calculated using the imputation dosage for each risk allele based on the results of the following GWAS: SCZ [[8]], BD [[9]], MDD [[10]], and SA [[6]]. However, our positive results could derive not only from the proportion of individuals with a previous diagnosis of SCZ or BD in our sample of suicide completers but also from the shared genetic bases between SB and these psychiatric disorders. Keywords: Completed suicide; Polygenic risk score; Schizophrenia; Bipolar disorder; Major depressive disorder; Suicide attempt EN Completed suicide Polygenic risk score Schizophrenia Bipolar disorder Major depressive disorder Suicide attempt 355 358 4 03/24/22 20220401 NES 220401 Marina Mitjans and Sergi Papiol are co-first authors; Bárbara Arias and Antoni Benabarre are co-last authors. [Extracted from the article]

Endoplasmic reticulum (ER) stress has been implicated in a variety of cardiovascular diseases. During ER stress, disruption of the complex of protein phosphatase 1 regulatory subunit 15A and catalytic subunit of protein phosphatase 1 by the small molecule guanabenz (antihypertensive, α2-adrenoceptor agonist) and subsequent inhibition of stress-induced dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in prolonged eIF2α phosphorylation, inhibition of protein synthesis and protection from ER stress. In this study we assessed whether guanabenz protects against ER stress in cardiac myocytes and affects the function of 3 dimensional engineered heart tissue (EHT). We utilized neonatal rat cardiac myocytes for the assessment of cell viability and activation of ER stress-signalling pathways and EHT for functional analysis. (i) Tunicamycin induced ER stress as measured by increased mRNA and protein levels of glucose-regulated protein 78 kDa, P-eIF2α, activating transcription factor 4, C/EBP homologous protein, and cell death. (ii) Guanabenz had no measurable effect alone, but antagonized the effects of tunicamycin on ER stress markers. (iii) Tunicamycin and other known inducers of ER stress (hydrogen peroxide, doxorubicin, thapsigargin) induced cardiac myocyte death, and this was antagonized by guanabenz in a concentration- and time-dependent manner. (iv) ER stressors also induced acute or delayed contractile dysfunction in spontaneously beating EHTs and this was, with the notable exception of relaxation deficits under thapsigargin, not significantly affected by guanabenz. The data confirm that guanabenz interferes with ER stress-signalling and has protective effects on cell survival. Data show for the first time that this concept extends to cardiac myocytes. The modest protection in EHTs points to more complex mechanisms of force regulation in intact functional heart muscle. [ABSTRACT FROM AUTHOR]

The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.1 associated with major mood disorders (rs2251219, P = 3.63 × 10−8; odds ratio = 0.87; 95% confidence interval, 0.83–0.92), with supportive evidence for association observed in two out of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for bipolar disorder and MDD. [ABSTRACT FROM AUTHOR]

Lithium-treated patients often suffer from weight gain as a common adverse event. In an earlier investigation, we found an impact of two single-nucleotide polymorphisms (rs10487506 and rs2278815) at the leptin gene on weight gain but not on leptin protein levels in serum under lithium augmentation. A recent genome-wide association study identified a polymorphism at the leptin gene locus (rs10487505) associated with circulating leptin protein levels. To characterize potential effects of this variant in acute major depressive disorder, we investigated body mass indices from 180 lithium-augmented patients and serum concentrations of leptin protein from 89 patients using linear mixed model analyses and rs6979832, a proxy SNP of rs10487505. Body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and 7 months. Leptin serum levels were measured before and during lithium augmentation. G-allele homozygotes of rs6979832 had a significantly lower body mass index increase during observation compared to A-allele hetero- and homozygotes. However, we found no influence on leptin serum levels. Joint analyses of rs6979832 with the previously investigated polymorphisms rs10487506 and rs2278815, and expressed quantitative trait data, suggest a complex interplay between SNP alleles at the leptin locus. These results strongly support our earlier findings that common genetic variation at the leptin gene locus may be involved in lithium augmentation-associated weight gain in major depressive disorder. [ABSTRACT FROM AUTHOR]

We have investigated the gene for dystrobrevin-binding protein 1 (DTNBP1), or dysbindin, which has been strongly suggested as a positional candidate gene for schizophrenia, in three samples of subjects with schizophrenia and unaffected control subjects of German (418 cases, 285 controls), Polish (294 cases, 113 controls), and Swedish (142 cases, 272 controls) descent. We analyzed five single-nucleotide polymorphisms (P1635, P1325, P1320, P1757, and P1578) and identified significant evidence of association in the Swedish sample but not in those from Germany or Poland. The results in the Swedish sample became even more significant after a separate analysis of those cases with a positive family history of schizophrenia, in whom the five-marker haplotype A-C-A-T-T showed a P value of .00009 (3.1% in controls, 17.8% in cases; OR 6.75; P = .00153 after Bonferroni correction). Our results suggest that genetic variation in the dysbindin gene is particularly involved in the development of schizophrenia in cases with a familial loading of the disease. This would also explain the difficulty of replicating this association in consecutively ascertained case-control samples, which usually comprise only a small proportion of subjects with a family history of disease. [ABSTRACT FROM AUTHOR]