Psychiatric Genetics Before "Genetics"

I write this in terrible times. Across the world, a pandemic rages nearly unchecked when simple behavioral changes could save many lives. Psychiatric disorders and their sequalae have sharply increased. The role of science, logic, data, and expertise have been pushed to the curb in favor of those who shout loudest

Uncovering the Genetic Architecture of Major Depression

There have been several recent studies addressing the genetic architecture of depression. This review serves to take stock of what is known now about the genetics of depression, how it has increased our knowledge and understanding of its mechanisms, and how the information and knowledge can be leveraged to improve the care of people affected. We identify four priorities for how the field of MD genetics research may move forward in future years, namely by increasing the sample sizes available for genome-wide association studies (GWASs), greater inclusion of diverse ancestries and low-income countries, the closer integration of psychiatric genetics with electronic medical records, and the development of the neuroscience toolkit for polygenic disorders. A review by McIntosh et al. takes stock of recent rapid progress in the genetics of depression, how it has increased our mechanistic understanding, and how this information could be used to improve patient care in future

Lifetime anxiety disorders in women with bulimia nervosa

We examined the prevalence and ages at onset of additional childhood and adult psychiatric disorders in women with bulimia nervosa and evaluated the differential impact of a mood or anxiety disorder on the presentation of bulimia nervosa. One hundred fourteen women participating in a clinical trial of cognitivebehavioral therapy for bulimia nervosa were assessed at pretreatment with structured diagnostic methodology. Although mood disorders were the most frequently occurring additional psychiatric disorder (75%), 64% experienced an additional anxiety disorder. Age at onset of the anxiety disorders was markedly earlier than age at onset of bulimia nervosa or other comorbid conditions. Stratification of the sample on the presence of a mood or anxiety disorder revealed no differences in the core bulimic symptoms across groups. The presence of a mood disorder was associated with greater body dissatisfaction, lower Global Assessment of Functioning Scales (GAFS) score, more externalizing disorders of childhood, and, as expected, higher Hamilton Depression Rating Scale (HDRS) scores. The presence of an anxiety disorder was related to a history of anorexia nervosa and earlier age at onset of drug or alcohol dependence. Early-onset anxiety disorders are prevalent and may represent one potential pathway to bulimia nervosa

A Munc18-1 mutant mimicking phosphorylation by Down Syndrome-related kinase Dyrk1a supports normal synaptic transmission and promotes recovery after intense activity

Phosphorylation of Munc18-1 (Stxbp1), a presynaptic organizer of synaptic vesicle fusion, is a powerful mechanism to regulate synaptic strength. Munc18-1 is a proposed substrate for the Down Syndrome-related kinase dual-specificity tyrosine phosphorylation-regulate kinase 1a (Dyrk1a) and mutations in both genes cause intellectual disability. However, the functional consequences of Dyrk1a-dependent phosphorylation of Munc18-1 for synapse function are unknown. Here, we show that the proposed Munc18-1 phosphorylation site, T479, is among the highly constrained phosphorylation sites in the coding regions of the gene and is also located within a larger constrained coding region. We confirm that Dyrk1a phosphorylates Munc18-1 at T479. Patch-clamp physiology in conditional null mutant hippocampal neurons expressing Cre and either wildtype, or mutants mimicking or preventing phosphorylation, revealed that synaptic transmission is similar among the three groups: frequency/amplitude of mEPSCs, evoked EPSCs, paired pulse plasticity, rundown kinetics upon intense activity and the readily releasable pool. However, synapses expressing the phosphomimic mutant responded to intense activity with more pronounced facilitation. These data indicate that Dyrk1a-dependent Munc18-1 phosphorylation has a minor impact on synaptic transmission, only after intense activity, and that the role of genetic variation in both genes in intellectual disability may be through different mechanisms

Predictors of 1-year treatment outcome in bulimia nervosa

We examined predictors of outcome 1 year after completion of a randomized clinical trial assessing the additive efficacy of two forms of exposure with response prevention to a core of cognitive-behavioral therapy (CBT) for bulimia nervosa (BN). One hundred one women who met DSM-III-R criteria for BN, and who completed the clinical trial, were available for follow-up at 1 year. Predictor variables were assessed prospectively and partitioned temporally to reflect lifetime history (including personality), pretreatment clinical status, and posttreatment clinical status. Outcome was based on the frequency of hinging and purging in the 3 months before assessment based on carefully constructed lifechart interviews. A series of stepwise logistic regressions were performed to determine independent predictors of 1-year outcome while controlling for treatment received. Demographic variables were unrelated to treatment outcome. A history of obesity was predictive of poor outcome, whereas a history of alcohol dependence decreased the odds of poor outcome. High self-directedness on the Temperament and Character Inventory (TCI) predicted favorable outcome at 1 year, whereas personality disorder symptoms were not predictive. Pretreatment global functioning, bulimia scores on the Eating Disorders Inventory (EDI), and the presence of major depression predicted poor outcome. Posttreatment binging, food restriction, and urges to binge on a cue reactivity assessment predicted poor outcome at 1 year. The character trait of self-directedness is a strong predictor of good outcome for CBT, and methods to enhance this trait may be worthy of investigation. Low global functioning and the presence of major depression at presentation may require additional treatment than focused CBT for BN. Our results argue for treatment goals that include abstinence from binging and restricting and decreases in urges to binge in response to high-risk cues

The longitudinal effects of stress and fear on psychiatric symptoms in mothers during the COVID-19 pandemic

The COVID-19 pandemic has been particularly difficult for mothers. Women with a history of peripartum depression (PPD) may be vulnerable to relapse. We sought to understand changes in depressive and anxious symptoms throughout the pandemic and which stressors increased symptoms in women with a history of PPD. In June 2020, all US participants with a history of PPD (n = 12,007) in the global MomGenes Fight PPD study were invited to the COVID-19 follow-up study. Respondents (n = 2163, 18%) were sent biweekly and then monthly surveys until January 31, 2022. We employed time-varying effects models to evaluate trajectories of depressive (patient health questionnaire, PHQ-9) and anxious (generalized anxiety disorder, GAD-7) symptoms and to estimate longitudinal associations between perceived stress, fears, COVID-19 case rates, and symptoms. Peaks of PHQ-9, GAD-7, PSS, and perceived COVID-19 risk scores corresponded with timing of national COVID-19 case surges. High perceived stress was the strongest predictor of PHQ-9 (beta = 7.27; P = 1.48e − 38) and GAD-7 (beta = 7.73; P = 6.19e − 70). Feeling lack of control and unlikely to survive increased PHQ-9 and GAD-7 scores by 2 points. COVID-19 case rates, pandemic restrictions, and region were not independently associated with symptoms. This study suggests that the collective trauma of the pandemic has significantly affected mothers with a history of PPD, exemplified by high levels of perceived stress and the strong association with depressive and anxious symptoms. The next pandemic phase is uncertain, but will continue to influence mental health collectively and dynamically. Interventions must be flexible and responsive and should address fear, trauma, and feelings of control, particularly for mothers with a history of PPD

Chronicity and Sex Affect Genetic Risk Prediction in Schizophrenia

Schizophrenia (SCZ) is a severe mental disorder with immense personal and societal costs; identifying individuals at risk is therefore of utmost importance. Genomic risk profile scores (GRPS) have been shown to significantly predict cases-control status. Making use of a large-population based sample from Sweden, we replicate a previous finding demonstrating that the GRPS is strongly associated with admission frequency and chronicity of SCZ. Furthermore, we were able to show a substantial gap in prediction accuracy between males and females. In sum, our results indicate that prediction accuracy by GRPS depends on clinical and demographic characteristics

Automorphism groups of polycyclic-by-finite groups and arithmetic groups

We show that the outer automorphism group of a polycyclic-by-finite group is an arithmetic group. This result follows from a detailed structural analysis of the automorphism groups of such groups. We use an extended version of the theory of the algebraic hull functor initiated by Mostow. We thus make applicable refined methods from the theory of algebraic and arithmetic groups. We also construct examples of polycyclic-by-finite groups which have an automorphism group which does not contain an arithmetic group of finite index. Finally we discuss applications of our results to the groups of homotopy self-equivalences of K(\Gamma, 1)-spaces and obtain an extension of arithmeticity results of Sullivan in rational homotopy theory

Unravelling the link between sleep and mental health during the COVID-19 pandemic

The emergence of COVID-19 brought unparalleled changes in people's lifestyle, including sleep. We aimed to assess the bidirectional association between sleep quality and mental health and describe how sleep and mental health were affected in Sweden during the COVID-19 pandemic (between June 2020 and September 2021). Data were obtained from the Omtanke2020 study. Participants who completed the baseline survey and each of the 8 monthly follow-up surveys were included (N = 9035). We described the distribution of sleep and mental health in the different Swedish regions using maps and over the study period with longitudinal graphs adjusting for sex, age, recruitment type (self-recruitment or invitation), and COVID-19 status. The inner relationships between mental health, sleep and Covid infection were described through relative importance networks. Finally, we modelled how mental health affects sleep and vice versa using generalized estimating equations with different adjustments. Seasonal and north-south regional variations were found in sleep and mental health outcomes at baseline and attenuated over time. The seasonal variation of sleep and mental health correlated moderately with the incidence rate of COVID-19 in the sample. Networks indicate that the relationship between COVID-19 incidence and mental health varies over time. We observed a bidirectional relationship between sleep quality and quantity at baseline and mental health at follow-up and vice versa. Sleep quality and quantity at baseline was associated with adverse symptom trajectories of mental health at follow-up, and vice versa, during the COVID-19 pandemic. There was also a weak relationship between COVID-19 incidence, sleep, and mental health

Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa

OBJECTIVE: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. RESULTS: Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. CONCLUSIONS: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology