Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects

Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D 2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Locking life-cycles to seasons : circle-map models of population dynamics and local adaptation

We have formulated a model describing the timing of maturity and reproduction in briefly semelparous organisms whose development rate is primarily controlled by environmental factors. The model is expressed as a circle-map relating time of year at maturation in successive generations. The properties of this map enable us to determine the degree of synchrony to be expected between the life-cycles of members of a population exposed to a regular seasonal environment. We have proved that organisms with a life-history composed of a contiguous series of stages, all with development driven by the same seasonal function, cannot phase-lock their life-cycles to the seasons. However if the organism exhibits facultative diapause induced by a critical time/critical development mechanism of the type proposed by Norling (1984a,b,c) then it will always succeed in phase-locking to a perfectly periodic driving function. Within the context of this circle-map model we have examined population extinctions caused by attempting to over-winter in an inappropriate life-history stage, or by attempting to reproduce at a time of year when this is impossible. We have shown that the possibility of such extinctions limits both the shortness of the post-critical stage, and the lateness of the critical time. We have examined the fitness of persistent cohorts as a function of critical time and development. We find that if the post-critical stage is riskier than the pre-critical then natural selection favors a short post-critical stage and a late critical time; the limitation of this process being dependent on the proportion of the growing season over which successful reproduction is possible. We have determined the variation with life-cycle length (and hence latitude or altitude) of the maturation pattern corresponding to optimal life-history parameters. We find that for organisms which can mature only over a small part of the growing season the majority of any latitudinal gradient exhibits a unimodal maturation pattern. Organisms which can mature and reproduce over the majority of the growing season exhibit more complex patterns, but still exhibit substantial ranges of latitude over which unimodal or bimodal patterns are optimal

Stage-specific quiescence as a mechanism for synchronising life cycles to seasons

Seasonal dormancy plays a critical role in synchronizing life cycles to seasons. In previous work, however, we have shown that quiescence-the readily reversible cessation of development in direct response to contemporaneous environmental conditions-acting alone and independent of stage development cannot yield synchronization. Here we demonstrate how stage-specific quiescence(SSQ), with stage dependence based solely on developmental thresholds that differ among stages, is generally sufficient to synchronize semelparous life cycles to seasons. We present an example consistent with this mechanism, compare SSQ with mechanisms based on diapause, and propose some testable hypotheses. Finally, we indicate additional empirical and theoretical work needed to evaluate the applicability of SSQ and its close relatives to a potentially wide range of organisms

Population regulation in animals with complex life-histories : formulation and analysis of a damselfly model

This chapter discusses population regulation in animals with complex life-historie