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

The state of the science in psychiatric genomics

The awfulness of 2020 has been described with eloquence and detail by many authors around the world. Put simply, at nearly every turn, events went in the wrong direction. So, it is nice to report a 2020 project that went well – in fact, for a change, something that went wonderfully better than expected

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

Editorial overview: Rare CNV disorders and neuropsychiatric phenotypes: opportunities, challenges, solutions

In this issue, our outstanding colleagues review the recent exponential growth in our understanding of copy number variants (CNV) in neuropsychiatric disorders. The impact of DNA dosage changes on phenotypic traits was first understood, and leveraged for genetic mapping, by Drosophila geneticists nearly a century ago. Evidence for DNA dosage changes influencing human phenotypes came several decades later with the observation that Down Syndrome is caused by an extra copy of chromosome 21. This was followed by discoveries that dosage changes far smaller than the scale of a whole chromosome, limited to smaller sets of genes, could also cause clinical syndromes. These hallmark syndromes have set the stage for our current understanding of CNV disorders, and in this issue, we review several classic syndromes, including Williams syndrome or 7q11.23 deletion, reviewed by Osbourne and Mervis; 22q11 deletion syndrome reviewed by Gur et al; and 16p11.2 deletion/duplication, reviewed by Chung and colleagues. DNA dosage changes can also affect single genes; the impact of NRXN1 dosage changes is reviewed by Fuccillo and Pak

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

The Genomics of Electroconvulsive Therapy International Consortium (GenECT-ic)

Despite large variation in clinical phenotypes and illness severity and heritability estimates of major depressive disorder ranging between 40% and 70%

The international postpartum depression: action towards causes and treatment (PACT) consortium

The International Postpartum depression: Action towards Causes and Treatment (PACT) Consortium was founded with the overarching goal of creating an international perinatal psychiatry consortium to conduct novel investigations with large sample sizes to understand the genetic signature of perinatal mood disorders. PACT uses a collaborative and team science approach that includes investigators across 19 institutions and seven continents. The large sample sizes allow for statistically rigorous analyses to investigate perinatal psychiatric disorders, with an initial focus on postpartum depression (PPD). Our current aims are to identify clinical sub-types of PPD that contribute diagnostic heterogeneity, and to elucidate the genetic basis of PPD by conducting the first large genome-wide association study of PPD. To accomplish the latter aim, we are partnering with the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. To date, our consortium members have recruited 17,912 participants and 11,344 participants have been identified using the PPD ACT mobile app, of which 8,432 are PPD cases. Ultimately, we hope this approach will improve detection, diagnosis, and treatment of women who suffer from perinatal psychiatric disorders

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

Swedish large-scale schizophrenia study: Why do patients and healthy controls participate?

Insights into determination of study participation are useful for researchers, clinicians and for ethical considerations. Few large-scale genomic studies have involved motives for enrollment, in schizophrenia patients and unaffected controls. In a case-control study with participants recruited nation-wide in Sweden between 2005 and 2010, semi-structured interviews on motives and attitudes towards future studies were explored in 2767 schizophrenia cases and 4466 controls. In qualitative and quantitative analyses, we identified altruism as a major determinant in 84% of the cases and in 97% of the controls. Among pre-defined subcategories of altruism, cases with schizophrenia were more often referring to science for example, ‘I want to help science move forward’ or ‘I want better medications for future generations’ in relation to unaffected controls that were more often referring to common humanity such as ‘It is my duty and responsibility to help’. In schizophrenia, motives related to personal benefit and social influence were reported by 9% and 5%. We conclude that individuals with schizophrenia frequently report altruistic motives for study participation, almost to the same extent as unaffected controls. In contrast to unfortunate stereotypes, people with schizophrenia wish others to benefit from their experiences with severe mental illness and should not be refrained from participating in genomic research

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