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Introduction: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. Methods: Genomic analyses were performed in 171 men and women aged 18–85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. Results: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer’s disease had a significantly decreased likelihood of relapse. Conclusion: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.

Background: Bipolar disorder (BD) is a clinical risk factor for Alzheimer’s disease (AD). Apolipoprotein E ε4 ( APOE ε4), a genetic risk factor for AD, has been associated with brain structure and neurocognition in healthy youth. Aims: We evaluated whether there was an association between APOE ε4 with neurostructure and neurocognition in youth with BD. Methods: Participants included 150 youth (78 BD:19 ε4-carriers, 72 controls:17 ε4-carriers). 3T-magnetic resonance imaging yielded measures of cortical thickness, surface area, and volume. Regions-of-interest (ROI) and vertex-wise analyses of the cortex were conducted. Neurocognitive tests of attention and working memory were examined. Results: Vertex-wise analyses revealed clusters with a diagnosis-by- APOE ε4 interaction effect for surface area ( p = 0.002) and volume ( p = 0.046) in pars triangularis (BD ε4 -carriers > BD noncarriers), and surface area ( p = 0.03) in superior frontal gyrus (controls ε4 -carriers > other groups). ROI analyses were not significant. A significant interaction effect for working memory ( p = 0.001) appeared to be driven by nominally poorer performance in BD ε4 -carriers but not control ε4 -carriers; however, post hoc contrasts were not significant. Conclusions: APOE ε4 was associated with larger neurostructural metrics in BD and controls, however, the regional association of APOE ε4 with neurostructure differed between groups. The role of APOE ε4 on neurodevelopmental processes is a plausible explanation for the observed differences. Future studies should evaluate the association of APOE ε4 with pars triangularis and its neurofunctional implications among youth with BD.

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.

Canada exhibits one of highest lifetime prevalence for post-traumatic stress disorder (PTSD), but the etiology of this debilitating mental health condition still remains largely unknown. This study aims to examine the genetics of PTSD in the Canadian Longitudinal Study on Aging (CLSA) to identify potential genetic factors involved in the development of PTSD.The CLSA sample was screened for primary (PTSD status) and secondary outcomes (avoidance, detachment, guardedness, and nightmares) based on the Primary Care PTSD Screen Scale (PC-PTSD). After GWAS quality control and whole-genome imputation, single-marker, gene-based, and polygenic risk score (PRS) analyses were performed.Based on available genotype and phenotype data, N = 16,535 individuals were selected for the analyses. While genome-wide analyses did not show significant findings for our primary and secondary outcomes, PRS analyses showed variable levels of association between PC-PTSD items with trauma, major depressive disorder, schizophrenia, bipolar disorder, educational attainment, and insomnia (p lt; 5e-4).This is the first GWAS of PTSD status and individual PC-PTSD items in a population sample of older adults from Canada. This study was also able to replicate findings from previous studies. Genetic investigations into individual symptom components of PTSD may help untangle the complex genetic architecture of PTSD.

Attention-deficit/hyperactivity disorder (ADHD) is a common and impairing neurodevelopmental disorder in which genetic factors play an important role. DNA sequencing of parent-child trios provides a powerful approach for identifyingde novo(spontaneous) variants, which has led to the discovery of hundreds of clinically informative risk genes for other neurodevelopmental disorders but has yet to be extensively leveraged in studying ADHD. Here, we conducted whole-exome DNA sequencing in 152 parent-child trios with ADHD and demonstrate for the first time a significant enrichment of rare and ultra-rarede novoprotein-truncating variants and missense variants predicted to be damaging in ADHD cases compared to unaffected controls. Combining these results with a large independent case-control DNA sequencing cohort (3,206 ADHD cases and 5,002 controls), we identifylysine demethylase 5B(KDM5B)as a high-confidence risk gene for ADHD as well as two likely risk genes. We estimate that 862 genes contribute to ADHD risk. Finally, using our list of genes harboring ultra-rarede novodamaging variants, we show that these genes overlap with previously reported risk genes for other neuropsychiatric conditions in both DNA sequencing and genome-wide association studies. We also show that these genes are enriched for several canonical biological pathways, suggesting early neurodevelopmental underpinnings of ADHD. Overall, this work provides critical new insight into the biology of ADHD and demonstrates the discovery potential of DNA sequencing in larger parent-child trio cohorts.Significance statementGiven the important role of genetic factors in the development of attention-deficit/hyperactivity disorder (ADHD), research aimed at identifying risk genes can provide critical insight into underlying biological processes. We conducted whole-exome DNA sequencing in parent-child trios with ADHD, showing that these children have a significantly greater rate of rare and ultra-rarede novogene-damaging mutations compared to unaffected controls, expanding our understanding of the genetic landscape of ADHD. We then use this information to identifyKDM5Bas a high-confidence risk gene for ADHD and highlight several enriched biological pathways. This work advances our etiologic understanding of ADHD and illustrates a previously unexplored path for risk gene discovery in this common neurodevelopmental disorder.

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

The lessons and recommendations described here were developed from conducting a research audit of the Transparent Psi Project (TPP). The TPP was intended as a potential model and learning experience for optimal research practices. The topics discussed here are among the potential lessons from the TPP. The recommendations are: (1) Validation of data collection software is essential. (2) Evaluation of power or operating characteristics (inferential errors) is essential, including for sequential Bayesian analyses. (3) An online repository copy of data is very valuable, but easy-to-use, reliable, secure processes remain to be developed. (4) A good research audit is much more extensive than current peer review for publication, including Registered Reports. (5) Quality control (QC) comes before auditing. (6) Good research practice guidelines and/or standard operating procedures (SOPs) for general use would be very valuable for confirmatory psychological research. (7) It is time to implement routine measures to prevent experimenter fraud. (8) Git appears to be not optimal for software tracking to prevent programming fraud.

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Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSCs by activating stress myelopoiesis, such roles in LSCs are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator that drives myeloid differentiation and activates inflammatory programs in both HSCs and LSCs. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across cohorts of patients with AML, each with distinct phenotypic and clinical properties. S1PR3 was high in LSCs and blasts of mature myeloid samples with linkages to chemosensitivity, whereas S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.Significance:S1PR3 is a novel regulator of myeloid fate in normal hematopoiesis that is heterogeneously expressed in AML. S1PR3 marks a subset of less primitive AML cases with a distinct inflammatory signature and therefore has clinical implications as both a therapeutic target and a biomarker to distinguish primitive from mature AML.See related commentary by Yang et al., p. 3.This article is highlighted in the In This Issue feature, p. 1

The treatment landscape of acute myeloid leukemia (AML) is evolving, with promising therapies entering clinical translation, yet patient responses remain heterogeneous, and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy makeup from bulk transcriptomes of more than 1,000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor and mature cell types. Leukemia hierarchy composition was associated with functional, genomic and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP and Intermediate. Critically, variation in hierarchy composition along the Primitive versus GMP or Primitive versus Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A seven-gene biomarker derived from the Primitive versus Mature axis was associated with response to 105 investigational drugs. Cellular hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.

Many promising new cancer drugs proceed through preclinical testing and early-phase trials only to fail in late-stage clinical testing. Thus, improved models that better predict survival outcomes and enable the development of biomarkers are needed to identify patients most likely to respond to and benefit from therapy. Here, we describe a comprehensive approach in which we incorporated biobanking, xenografting, and multiplexed phospho-flow (PF) cytometric profiling to study drug response and identify predictive biomarkers in acute myeloid leukemia (AML) patients. To test the efficacy of our approach, we evaluated the investigational JAK2 inhibitor fedratinib (FED) in 64 patient samples. FED robustly reduced leukemia in mouse xenograft models in 59% of cases and was also effective in limiting the protumorigenic activity of leukemia stem cells as shown by serial transplantation assays. In parallel, PF profiling identified FED-mediated reduction in phospho-STAT5 (pSTAT5) levels as a predictive biomarker of in vivo drug response with high specificity (92%) and strong positive predictive value (93%). Unexpectedly, another JAK inhibitor, ruxolitinib (RUX), was ineffective in 8 of 10 FED-responsive samples. Notably, this outcome could be predicted by the status of pSTAT5 signaling, which was unaffected by RUX treatment. Consistent with this observed discrepancy, PF analysis revealed that FED exerted its effects through multiple JAK2-independent mechanisms. Collectively, this work establishes an integrated approach for testing novel anticancer agents that captures the inherent variability of response caused by disease heterogeneity and in parallel, facilitates the identification of predictive biomarkers that can help stratify patients into appropriate clinical trials. Cancer Res; 76(5); 1214–24. ©2016 AACR.

Supplemental Methods Supplemental Table 1 Supplemental Figures 1-6 1. Pretreatment with cytarabine potentiates the effects of FED in AML xenografts. Supplemental Figure 2. PF cytometry analysis of AML samples. Supplemental Figure 3. Immunophenotypic and phosphoprotein signaling heterogeneity of AML patient samples. Supplemental Figure 4. PF analysis of validation cohort samples Supplemental Figure 5. Effects of FED treatment on FLT3 activity. Supplemental Figure 6. Effects of FED and DAS treatment on pSTAT5, pSRC and pTyr in BCR-ABL1+ AML samples. Supplemental Table 1: Characteristics of patient samples studied in initial and validation cohorts.

Background CACNA1C rs1006737 A allele, identified as a genetic risk variant for bipolar disorder (BD), is associated with anomalous functional connectivity in adults with and without BD. Studies have yet to investigate the association of CACNA1C rs1006737 with resting-state functional connectivity (rsFC) in youth BD. Methods Participants included 139 youth with BD-I, -II, or -not otherwise specified, ages 13–20 years, including 27 BD A-carriers, 41 BD non-carriers, 32 healthy controls (HC) A-carriers, and 39 HC non-carriers. Anterior cingulate cortex (ACC), amygdala, and orbitofrontal cortex (OFC) were examined as regions-of-interest in seed-to-voxel analyses. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and race. Results We observed a main effect of BD diagnosis on rsFC between the right amygdala and the right occipital pole (p = 0.02), and a main effect of rs1006737 genotypes on rsFC between the right OFC and bilateral occipital cortex (p p = 0.01), and negative rsFC between the left OFC and left putamen in BD but positive rsFC in HC (p = 0.01). Conclusion This study found that the rs1006737 A allele, identified as a genetic risk variant for BD in adults, was differentially associated with rsFC in youth with BD in regions relevant to emotion, executive function, and reward. Future task-based approaches are warranted to better understand brain connectivity in relation to CACNA1C in BD.

Information processing underlies all life and is a defining characteristic of life. Concepts of information are also increasingly proposed as underlying or having a role in the mysteries of quantum physics. However, scientific progress is hindered by different concepts, terminology, and assumptions about information in different branches of science and technology. The purpose of this paper is to identify and explore fundamental concepts of information that are applicable throughout the wide spectrum of uses of the term. The terms symbolic information and physical information are used here to distinguish between two fundamentally different concepts of information. Symbolic information is based on symbols created by living entities as part of processes for perception, memory, communication, purposeful action, or planning. Symbolic information has three components: symbolic representation, media, and interpretational infrastructure. Symbolic information is the mechanism for living entities to generate variability, adaptability, and creativity from the fixed, relatively deterministic forces of physics. Symbolic information processing is the fundamental reason that living systems have properties that are categorically different from the properties of nonliving matter. Living systems have layer upon layer of interacting symbolic information processing, from reproduction to imagination, creativity, and culture. The term physical information is used here for the concept that any physical non-uniformity, difference, or distinction is information. Physical information is a descriptive property of the distribution of matter and energy. Physical information is conceptually related to entropy in physics and does not consider whether different physical states have meaning for living beings or were created by living entities for use as symbols. The failure to distinguish between symbolic information and physical information often results in ambiguous, misleading concepts that (a) imply nonliving processes have properties of life, (b) undervalue the essential role of interpretation for symbolic information, and (c) do not recognize the creative potential of symbolic information processing. If the term information is proposed as an explanatory factor in physics, any implications that nonliving processes encode or interpret information must be carefully justified in context of the differences between symbolic and physical information.

The Kerrouchen Basin is an understudied rift basin in the Middle Atlas of Morocco, where over 600 m of Triassic stratigraphy is well exposed. It was partially inverted during the Atlasic orogeny whilst preserving the original basin geometry. Within the Kerrouchen Basin, two distinct fluvial systems are present. The first, recorded by the K3 Formation, is a braided-meandering fluvial system showing vertical and lateral amalgamation. The K3 is an axial fluvial system that shows a predominant drainage direction towards the north-north-east, parallel to the rift zone axis, ultimately draining towards the Tethys Ocean. The K4 Formation records a secondary, Tributary Fluvial System (TFS), with facies spanning a range of alluvial-fluvial processes. Paleoflows predominantly record drainage to the SSW, transverse to the basin axis. Heavy mineral and petrographic analysis of the two fluvial systems indicates two distinct sedimentary provenances for the depositional system. The K3 system records a higher proportion of sediment sourced from igneous rocks. In contrast, the K4 system records a local provenance signal derived from adjacent low-medium grade metamorphic terranes exposed to the east. Comparison of the provenance and stratigraphic trends within the Kerrouchen Basin with work undertaken in the Central and Western High Atlas suggests a shared source region for the through going axial fluvial systems recorded in the High Atlas and Kerrouchen basins. Our study provides evidence for a linked fluvial system spanning the High and Middle Atlas rifts during the Triassic, indicating that a regional fluvial system was present within Central Pangea from Middle-Late Triassic times. Identifying regional and local drainage networks within the Triassic rift basins has key implications for paleogeographic reconstructions and future exploration efforts for hydrocarbons and CCS sites within Morocco.

Pharmacogenetic investigations into the opioid crisis suggest genetic variation could be a significant cause of opioid- related morbidity and mortality. Variability in opioid system genes, including single nucleotide polymorphisms, manifest after pharmacogenetic testing, as previously invisible risk factors for addiction and overdose. Pharmacodynamic genes regulate opioid-sensitive brain networks and neural reward circuitry. Pharmacokinetic genes expressed in drug metabolic pathways regulate blood levels of active versus inactive opioid metabolites. Elucidating the complex interplay of genetic variations in pharmacokinetic and pharmacodynamic pathways will shed new light on the addictive and toxic properties of opioids. This narrative review serves to promote understanding of key genetic mechanisms affecting the metabolism and actions of opioids, and to explore causes of the recent surge in opioid-related mortality associated with COVID-19. Personalized treatment plans centred around an individual's genetic makeup could make opioid-based pain management and opioid use disorder (OUD) treatments safer and more effective at both the individual and system levels.