Somatosensory-Motor Dysconnectivity Spans Multiple Transdiagnostic Dimensions of Psychopathology, bioRxiv, 2019-05-16

AbstractBackgroundThere is considerable interest in a dimensional transdiagnostic approach to psychiatry. Most transdiagnostic studies have derived factors based only on clinical symptoms, which might miss possible links between psychopathology, cognitive processes and personality traits. Furthermore, many psychiatric studies focus on higher-order association brain networks, thus neglecting the potential influence of huge swaths of the brain.MethodsA multivariate data-driven approach (partial least squares; PLS) was utilized to identify latent components linking a large set of clinical, cognitive and personality measures to whole-brain resting-state functional connectivity (RSFC) patterns across 224 participants. The participants were either healthy (N=110) or diagnosed with bipolar disorder (N=40), attention-deficithyperactivity disorder (N=37), schizophrenia (N=29) or schizoaffective disorder (N=8). In contrast to traditional case-control analyses, the diagnostic categories were not utilized in the PLS analysis, but were helpful for interpreting the components.ResultsOur analyses revealed three latent components corresponding to general psychopathology, cognitive dysfunction and impulsivity. Each component was associated with a unique whole-brain RSFC signature and shared across all participants. The components were robust across multiple control analyses and replicated using independent task functional magnetic resonance imaging data from the same participants. Strikingly, all three components featured connectivity alterations within the somatosensory-motor network, and its connectivity with subcortical structures and cortical executive networks.ConclusionsWe identified three distinct dimensions with dissociable (but overlapping) whole-brain RSFC signatures across healthy individuals and individuals with psychiatric illness, providing potential intermediate phenotypes that span across diagnostic categories. Our results suggest expanding the focus of psychiatric neuroscience beyond higher-order brain networks.

biorxiv neuroscience 0-100-users 2019

The Paraventricular Thalamus is a Critical Mediator of Top-down Control of Cue-motivated Behavior in Rats, bioRxiv, 2019-05-14

AbstractCues in the environment can elicit complex emotional states, and thereby maladaptive behavior, as a function of their ascribed value. Here we capture individual variation in the propensity to attribute motivational value to reward-cues using the sign-trackergoal-tracker animal model. Goal-trackers attribute predictive value to reward-cues, and sign-trackers attribute both predictive and incentive value. Using chemogenetics and microdialysis, we show that, in sign-trackers, stimulation of the neuronal pathway from the prelimbic cortex (PrL) to the paraventricular nucleus of the thalamus (PVT) decreases the incentive value of a reward-cue. In contrast, in goal-trackers, inhibition of the PrL-PVT pathway increases both the incentive value and dopamine levels in the nucleus accumbens shell. The PrL-PVT pathway, therefore, exerts top-down control over the dopamine-dependent process of incentive salience attribution. These results highlight PrL-PVT pathway as a potential target for treating psychopathologies associated with the attribution of excessive incentive value to reward-cues, including addiction.

biorxiv neuroscience 0-100-users 2019

Dsuite - fast D-statistics and related admixture evidence from VCF files, bioRxiv, 2019-05-11

AbstractSummaryThe D-statistic, also known as the ABBA-BABA statistic, and related statistics are commonly used to assess evidence of gene flow between populations or closely related species. While the calculations are not computationally intensive, currently available implementations require custom file formats and are impractical to evaluate all gene flow hypotheses across datasets that include many populations or species. Dsuite is a fast C++ implementation, allowing genome scale calculations of the D-statistic across all combinations of tens or even hundreds of populations or species directly from a variant call format (VCF) file. Furthermore, the program can estimate the admixture fraction and provide evidence of whether introgression is confined to specific loci. Thus Dsuite facilitates assessment of gene flow across large genomic datasets.Availability and implementationSource code and documentation are available at <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpsgithub.commillanekDsuite>httpsgithub.commillanekDsuite<jatsext-link>

biorxiv genomics 0-100-users 2019

Fine-scale haplotype structure reveals strong signatures of positive selection in a recombining bacterial pathogen, bioRxiv, 2019-05-11

ABSTRACTIdentifying the forces that create and shape ecologically meaningful variation in bacteria remains an important challenge. For recombining bacteria, the sign and strength of linkage provide a unique lens into ongoing selection. We show derived alleles less than 300bp apart in Neisseria gonorrhoeae exhibit more coupling linkage than repulsion linkage, a pattern that cannot be explained by limited recombination or neutrality as these couplings are significantly stronger for nonsynonymous alleles compared to synonymous alleles. While linkage is shaped by many evolutionary processes, extensive simulations show only two distinct forms of positive selection can drive an excess of coupling linkage between neighboring nonsynonymous alleles directional selection on introgressed alleles or selection that maintains distinct haplotypes in the presence of recombination. Our results establish a framework for identifying patterns of selection in fine-scale haplotype structure that indicate specific ecological processes in species that recombine with distantly related lineages or possess coexisting adaptive haplotypes.

biorxiv evolutionary-biology 0-100-users 2019

Improved assembly and variant detection of a haploid human genome using single-molecule, high-fidelity long reads, bioRxiv, 2019-05-11

AbstractThe sequence and assembly of human genomes using long-read sequencing technologies has revolutionized our understanding of structural variation and genome organization. We compared the accuracy, continuity, and gene annotation of genome assemblies generated from either high-fidelity (HiFi) or continuous long-read (CLR) datasets from the same complete hydatidiform mole human genome. We find that the HiFi sequence data assemble an additional 10% of duplicated regions and more accurately represent the structure of tandem repeats, as validated with orthogonal analyses. As a result, an additional 5 Mbp of pericentromeric sequences are recovered in the HiFi assembly, resulting in a 2.5-fold increase in the NG50 within 1 Mbp of the centromere (HiFi 480.6 kbp, CLR 191.5 kbp). Additionally, the HiFi genome assembly was generated in significantly less time with fewer computational resources than the CLR assembly. Although the HiFi assembly has significantly improved continuity and accuracy in many complex regions of the genome, it still falls short of the assembly of centromeric DNA and the largest regions of segmental duplication using existing assemblers. Despite these shortcomings, our results suggest that HiFi may be the most effective stand-alone technology for de novo assembly of human genomes.

biorxiv genomics 0-100-users 2019

Jumping To Conclusions, General Intelligence, And Psychosis Liability Findings From The Multi-Centre EU-GEI Case-Control Study, bioRxiv, 2019-05-11

AbstractBackgroundThe “jumping to conclusions” (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ.Methods817 FEP patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC (assessed by the number of beads drawn on the probabilistic reasoning “beads” task) and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.ResultsThe estimated proportion of the total effect of casecontrol differences on JTC mediated by IQ was 79%. Schizophrenia Polygenic Risk Score (SZ PRS) was non-significantly associated with a higher number of beads drawn (B= 0.47, 95% CI −0.21 to 1.16, p=0.17); whereas IQ PRS (B=0.51, 95% CI 0.25 to 0.76, p&lt;0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with higher level of psychotic-like experiences (PLE) in controls, including after controlling for IQ (B= −1.7, 95% CI −2.8 to −0.5, p=0.006), but did not relate to delusions in patients.Conclusionsthe JTC reasoning bias in psychosis is not a specific cognitive deficit but is rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to psychotic-like experiences, independent of IQ. The work has potential to inform interventions targeting cognitive biases in early psychosis.

biorxiv neuroscience 0-100-users 2019