Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

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LD score regression distinguishes confounding from polygenicity in genome-wide association studies :

The problem of which cues, internal or external, permit a person to label and identify his own emotional state has been with us since the days that James (1890) first tendered his doctrine that \"the bodily changes follow directly the perception of the exciting fact, and that our feeling of the same changes as they occur is the emotion\" (p. 449). Since we are aware of a variety of feeling and emotion states, it should follow from James' proposition that the various emotions will be accompanied by a variety of differentiable bodily states. Following James' pronouncement, a formidable number of studies were undertaken in search of the physiological differentiators of the emotions. The results, in these early days, were almost uniformly negative. All of the emotional states experi-

"Cognitive, social, and physiological determinants of emotional state": Erratum

Childhood trauma dependent anxious depression sensitizes HPA axis function

Abstract Symptoms of obsessive–compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive–compulsive symptoms (OCS) and ACTG1 -associated Baraitser-Winter cerebrofrontofacial syndrome has not been described as yet. A thoroughly phenotyped patient with OCS and ACTG1 -associated Baraitser-Winter cerebrofrontofacial syndrome is presented. The 25-year-old male patient was admitted to in-patient psychiatric care due to OCD. A whole-exome sequencing analysis was initiated as the patient also showed an autistic personality structure, below average intelligence measures, craniofacial dysmorphia signs, sensorineural hearing loss, and sinus cavernoma as well as subtle cardiac and ophthalmological alterations. The diagnosis of Baraitser-Winter cerebrofrontofacial syndrome type 2 was confirmed by the detection of a heterozygous likely pathogenic variant in the ACTG1 gene [c.1003C &gt; T; p.(Arg335Cys), ACMG class 4]. The automated analysis of magnetic resonance imaging (MRI) revealed changes in the orbitofrontal, parietal, and occipital cortex of both sides and in the right mesiotemporal cortex. Electroencephalography (EEG) revealed intermittent rhythmic delta activity in the occipital and right temporal areas. Right mesiotemporal MRI and EEG alterations could be caused by a small brain parenchymal defect with hemosiderin deposits after a cavernomectomy. This paradigmatic case provides evidence of syndromic OCS in ACTG1 -associated Baraitser-Winter cerebrofrontofacial syndrome. The MRI findings are compatible with a dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD. If a common pathophysiology is confirmed in future studies, corresponding patients with Baraitser-Winter cerebrofrontofacial syndrome type 2 should be screened for OCS. The association may also contribute to a better understanding of OCD pathophysiology. 

/pdf/obsessive-compulsive-symptoms-in-actg1-associated-baraitser-34p8z69b.pdf

Obsessive–compulsive symptoms in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome

OBJECTIVE
Previous diffusion tensor imaging studies reported a reduced fractional anisotropy in the body of the corpus callosum in patients with anorexia nervosa patients, which may indicate impaired white matter integrity in interhemispheric connections. The aim of the current study was to investigate whether structural connectivity is affected in patients with anorexia nervosa.


METHOD
To this end, we compared the number of streamlines (a model of the white matter fibre tracts) and the total volume filled by these streamlines in different subsections of the corpus callosum in 33 women with and 33 without anorexia nervosa as well as in 20 recovered individuals.


RESULTS
The volume of streamlines in the anterior and mid-anterior subsection of the corpus callosum was reduced in women with, but not in those who had recovered from anorexia nervosa. No differences in number of streamlines was detected in the corpus callosum between patients with anorexia nervosa, healthy controls and recovered patients.


CONCLUSIONS
Alterations of the corpus callosum have been repeatedly reported in anorexia nervosa. Since the recovered group did not differ from the healthy control group, the reported alterations in acute patients appear to represent a state and not a trait marker.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/erv.2894

Reduced structural connectivity in the corpus callosum in patients with anorexia nervosa.

Our genes, our choices - by David Goldman

Serotonergic influences on anterior cingulate cortex (ACC) functions have been described. In addition, functional polymorphisms in the promoter region of the serotonin transporter gene 5-HTTLPR are associated with increased vulnerability for major depressive disorder (MDD). Here we investigated whether 5-HTTLPR risk variants are related to abnormalities in ACC function observed in MDD, i.e. overactivation of the ACC during the performance of a working-memory task. Fifty-six healthy subjects and remitted MDD patients were investigated with a verbal n-back task using functional magnetic resonance imaging at 3 Tesla. The impact of genotype and group were analyzed in a full-factorial design. Carriers of risk variants and remitted MDD patients revealed ACC hyperactivation. The effect of genotype remained significant for healthy participants alone. Presence of MDD and presence of 5HTTLPR risk variants are associated with ACC dysregulation during the performance of a working-memory task. In healthy participants, presence of risk variants leads to a pattern of hyperactivation similar to overactivation in MDD, indicating that 5HTTLPR effects on ACC function may mediate vulnerability to depression.

Katharina Domschke

Papers

Childhood trauma dependent anxious depression sensitizes HPA axis function

Obsessive–compulsive symptoms in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome

Reduced structural connectivity in the corpus callosum in patients with anorexia nervosa.

Our genes, our choices - by David Goldman

Serotonin-transporter polymorphism modulates anterior cingulate cortex activation during working memory tasks – an fMRI study