Polygenic variation in sexual investment across an ephemerality gradient in Daphnia pulex

Species across the tree of life can switch between asexual and sexual reproduction. In facultatively sexual species, the ability to switch between reproductive modes is often environmentally dependent and subject to local adaptation. However, the ecological and evolutionary factors that influence the maintenance and turnover of polymorphism associated with facultative sex remain unclear. To address this basic question, we studied the ecological and evolutionary dynamics of polymorphism in reproductive strategy in a metapopulation of the model facultative sexual, Daphnia pulex, located in the southern United Kingdom. We found that patterns of clonal diversity, but not genetic diversity varied with ephemerality. Reconstruction of a multi-year pedigree demonstrated the co-existence of clones that were found to differ in their investment into male production. Mapping of quantitative variation in male production using lab-generated and field-collected individuals identified multiple putative QTL underlying this trait, and we identified a plausible candidate gene. The evolutionary history of these QTL suggests that they are relatively young, and male limitation in this system is a rapidly evolving trait. Our work highlights the dynamic nature of the genetic structure and composition of facultative sex across space and time and suggests that quantitative genetic variation in reproductive strategy can undergo rapid evolutionary turnover.

Monogenic and Polygenic Contributions to QTc Prolongation in the Population

Background: Rare sequence variation in genes underlying the long QT syndrome (LQTS) and common polygenic variation influence QT interval duration. It is unclear how rare and common variation contribute to QT interval duration in the general population. Objectives: Investigate monogenic and polygenic contributions to QT interval duration and the role of polygenic variation in modulating phenotypic expression of rare monogenic variation. Methods: We performed a genome wide association study (GWAS) of QTc duration in 44,979 United Kingdom Biobank (UKBB) participants and created a polygenic risk score (PRS). The PRS was validated in 39,800 independent UKBB participants. Among 26,976 participants with whole genome sequencing and ECG data in the TransOmics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 LQTS genes. We examined QTc associations with the PRS and with LQTS rare variants in TOPMed. Results: Twenty independent loci (4 novel) were identified by GWAS. The PRS comprising 565 common variants was significantly associated with QTc duration in TOPMed (p=1.1x10-64). Carriers of LQTS rare variants had longer QTc intervals than non-carriers (deltaQTc=10.9 ms [7.4-14.4] for all LQTS genes; deltaQTc=26.5 ms [20.7-32.3] for KCNQ1, KCNH2 and SCN5A). 16.7% of individuals with QTc>480 ms carried either a rare variant in a LQTS gene or had a PRS in the top decile (3.4% monogenic, 13.6% top decile of PRS). We observed a greater effect of rare variants on the QTc among individuals with a higher polygenic risk (lowest PRS tertile:deltaQTccarrier/non-carrier=4.8 ms [-1.2-10.7];highest PRS tertile:deltaQTccarrier/non-carrier=18.9 ms [12.8-25.1];p-interaction=0.001). Conclusions: QTc duration is influenced by both rare variants in established LQTS genes and polygenic risk. The phenotypic expression of monogenic variation is modulated by polygenic variation. Nevertheless, over 80% of individuals with prolonged QTc do not carry a rare monogenic variant or polygenic risk equivalent.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age

Background: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified. Aims: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval. Methods: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al. Results: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ßstd = 0.176, p < 0.001) and age (ßstd = 0.139, p < 0.001) with the QTc interval corrected according to Fridericia’s formula. Sex showed a nominal trend towards significance (ßstd = 0.064, p = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis ( n = 588) showed a significant association of potassium serum concentrations with the QTc interval (ßstd = −0.104, p = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis ( n = 26, ßstd = 0.101, p = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association. Conclusions: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.

Shared risk alleles with discordant polygenic effects: Disentangling the genetic overlap between ASD and ADHD

Insight into shared polygenetic architectures affects our understanding of neurodevelopmental disorders. Here, we investigate evidence for pleiotropic mechanisms that may explain the comorbidity between Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). These complex neurodevelopmental conditions often co-occur, but differ in their polygenetic association patterns, especially with educational attainment (EA), showing discordant association effects. Using multivariable regression analyses and existing genome-wide summary statistics based on 10,610 to 766,345 individuals, we demonstrate that EA-related polygenic variation is shared between ASD and ADHD. We show that different combinations of the same ASD and ADHD risk-increasing alleles can simultaneously re-capture known ASD-related positive and ADHD-related negative associations with EA. Such patterns, although to a lesser degree, were also present for combinations of other psychiatric disorders. These findings suggest pleiotropic mechanisms, where the same polygenic sites can encode multiple independent, even discordant, association patterns without involving distinct loci, and have implications for cross-disorder investigations.

Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing

BackgroundExternalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders.MethodsOne-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes.ResultsA polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs.ConclusionsFindings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.