Deborah Janowitz

Mouse genomic variation and its effect on phenotypes and gene regulation.

We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.

Sequence-based characterization of structural variation in the mouse genome.

Structural variation is widespread in mammalian genomes and is an important cause of disease, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1 kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

From Childhood Trauma to Adult Dissociation: The Role of PTSD and Alexithymia

Background: The mechanism of how childhood trauma leads to increased risk for adult dissociation is not sufficiently understood. We sought to investigate the predicting effects and the putatively mediating roles of PTSD and alexithymia on the path from childhood trauma to adult dissociation. Methods: A total of 666 day-clinic outpatients were administered the Childhood Trauma Questionnaire (CTQ), the Toronto Alexithymia Scale (TAS-20), the Posttraumatic Diagnostic Scale (PDS), and the Dissociative Experiences Scale (DES) and controlled for sex, age, and the Global Symptom Index (GSI). Linear regression analyses and mediation analyses were applied. Results: Independent predictive effects on dissociation were found for childhood trauma, alexithymia and PDS, even after adjusting for GSI. Effects of childhood neglect on dissociation were slightly stronger than of abuse. Alexithymia did not mediate the path from childhood trauma to dissociation. Mediation by PDS was specific for childhood abuse, with all PTSD symptom clusters being significantly involved. Conclusions: Childhood abuse and neglect are important predictors of dissociation. While the effects of abuse are mediated by PTSD, the mechanism of how neglect leads to dissociation remains unclear. The results further support the predictive value of alexithymia for adult dissociation above and beyond the effects of childhood trauma, PTSD, and GSI scores.

Childhood adversity impacts on brain subcortical structures relevant to depression

Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression.

Regional tract-specific white matter hyperintensities are associated with patterns to aging-related brain atrophy via vascular risk factors, but also independently

We sought to investigate associations of regional white matter hyperintensities (WMHs) within white matter (WM) tracts with cardiovascular risk and brain aging‐related atrophy throughout adulthood in the general population, leveraging state of the art pattern analysis methods.

Alexithymia and Psychotherapeutic Treatment Motivation: Main and Interactional Effects on Treatment Outcome

cluded due to discontinuation of the treatment program or missing data. Thus, an analytic sample of 518 patients, treated in 6 psychiatric day hospitals located in the region of Western Pomerania, Germany (all part of the University Hospital Greifswald), completed the German versions of the Toronto Alexithymia Scale 20 (TAS-20) [8] and the Symptom Checklist-90-Revised [9] to assess the global symptom severity (GSI) at admission (t 0 ) and discharge (t 1 ). Treatment motivation was assessed using the Questionnaire for the Measurement of Psychotherapy Motivation (FMP-30) at t 0 [7] . The treatment program included art therapy, relaxation therapy, and body and movement therapy on a daily basis. Each patient received an individual psychotherapy session of 1 h per week, with either a psychodynamic or cognitive-behavioral approach. Psychotropic medication was offered if clinically indicated. The duration of the treatment program ranged generally between 6 and 8 weeks. All patients gave written informed consent prior to inclusion in the study. Of the analytic sample, 70.2% were female, and the mean age was 43.1 years (SD 11.3). At admission, the mean TAS-20 score was 55.9 (SD 11.4); 185 subjects (35.7%) were alexithymic according to common TAS-20 cutoff scores of >60. Hierarchical linear regression analysis with sex, age, and GSIt 0 as control variables was applied to calculate the predictive power of TAS-20 and FMP subscales on GSIt 1 in the total sample ( Table 1 ). TAS-20 (β = 0.08; p = 0.035) and treatment expectations (β = –0.100; p = 0.009) were found as significant predictors of GSIt 1 . Partial correlation analyses of TAS-20 and the FMP subscales, adjusted for age, sex, and GSIt 0 , revealed significant negative correlations of TAS-20 and treatment expectations ( r = –0.116; p = 0.008), demonstrating that with increasing alexithymia scores perceived suitability and expected outcome of the treatment decrease. We also observed a significant positive correlation between TAS-20 and the degree of suffering ( r = 0.122; p = 0.005), showing that the perceived suffering is related with alexithymic personality features over and above GSI scores. Conditional regression analyses were performed to calculate interactional effects between TAS-20 (grouped variable, alexithymic vs. nonalexithymic) and each FMP subscale (z-standardized). Models were adjusted for sex, age, and GSIt 0 (z-standardized). We found a TAS-20 by “degree of suffering” interaction (β = 0.086; p = 0.019), showing that the treatment outcome of alexithymic patients is independent from the degree of suffering, while in nonalexithymic patients this PTM dimension is related with a more beneficial treatment outcome. Additional analysis of variance showed significant between-center effects on the treatment outcome. However, predictive effects of alexithymia and treatment motivation stayed stable. Consistent with previous studies, our results lend further support to the role of psychotherapeutic treatment expectations and alexithymia on the treatment outcome [4, 10] . However, the novAlexithymia is a personality style regularly found among patients seeking psychotherapeutic help and is associated with various psychiatric and psychosomatic disorders including depression [1] , somatization disorder [2] , and chronic somatoform pain [3] . While different studies found alexithymia to be associated with unbeneficial treatment outcome [1, 4] , the mechanism remains incompletely understood. Psychotherapeutic treatment motivation (PTM) has been suggested as a key factor for the acceptance of, adherence to, and engagement in psychotherapeutic processes across different methods and techniques [5, 6] . A recent concept of PTM includes the dimensions psychotherapeutic treatment expectations, degree of suffering, psychosocial lay etiology, and, as a negative motivational factor, secondary illness benefits [7] . Alexithymic subjects experience psychological distress as somatic symptoms which cannot be interpreted in a meaningful way. These patients may favor a more somatic causal model compared to psychosocial explanations for their complaints. Moreover, the attitudes of alexithymic patients towards psychotherapy and their expectations for the treatment outcome may be limited, which may reduce their treatment motivation. However, to our knowledge, no study has systematically investigated the relationship of alexithymia and dimensions of PTM in their effect on the treatment outcome. In detail, we investigated whether (1) alexithymia and the dimensions of PTM predicted the treatment outcome in terms of symptom reduction, (2) alexithymic personality features were correlated with the dimensions of PTM, and (3) alexithymia and dimensions of PTM interact in their effects on the treatment outcome. A total of 991 patients were consecutively admitted. Of these, 778 patients agreed to participate while 260 subjects had to be exReceived: December 15, 2016 Accepted after revision: January 24, 2017 Published online: May 11, 2017

Epidemiologie, Familiarität und Genetik der Zwangsstörung

Zusammenfassung: Zahlreiche epidemiologische Studien der letzten Jahre haben weltweit eine Lebenszeitpravalenz der Zwangsstorung von 1-3 % ermittelt. Es findet sich in der Allgemeinbevolkerung eine leicht erhohte Erkrankungsrate bei Frauen. Aktuelle kontrollierte Familienstudien zeigen eindeutig eine familiare Transmission der Zwangsstorung auf. Diese Befunde deuten, zusammen mit einigen allerdings methodisch schwacheren Zwillingsstudien, auf eine genetische Erkrankungsdisposition hin. Zahlreiche genetische Assoziationsstudien sind bislang bei der Zwangsstorung mit zumeist inkonsistenten Befunden durchgefuhrt worden. Gerade Kandidatengene des serotonergen und dopaminergen Systems zeigten keine konsistenten Assoziationen. In methodisch optimierten aktuellen Studien zeigten sich viel versprechende Assoziationen zu Polymorphismen des Glutamat-Transportergens (SLC1A1) und des OLIG2-Gens (Oligodendrocyte lineage transcription factor 2). Methodische Implikationen fur zukunftige genetische Untersuchungen bei der...

White matter lesions: Spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy

Objectives To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH). Methods MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22–84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression. Results WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the fifth decade of life, whereas the other components appeared later in life during the sixth decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in the elderly. Cognitive decline was associated with the dorsal component. Conclusions These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiologic mechanisms, and possibly with a differential link to vascular and neurodegenerative changes.

Psychotische Dekompensation, Substanzkonsum oder serotonerges Syndrom?

A young male with schizophrenia, dependence syndrome (multiple drug use) and a severe depressive episode develops a serotonin syndrome with Sertraline and Ziprasidone. Making the correct diagnosis, although potentially challenging, remains vital.