Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10501) and individuals with non-TRS (n = 20325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85490 participants (48635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P =.001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P =.04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance

L’agrophysiologie au service de la sélection et de l’agronomie. Le soja, un atout pour nos territoires

National audienc

L’agrophysiologie au service de la sélection et de l’agronomie. Le soja, un atout pour nos territoires

National audienc

Le semis très précoce : une stratégie agronomique pour améliorer les performances du soja en France ?

Le semis très précoce du soja a été étudié dans l’objectif d’améliorer le potentiel de rendement et/ou de réduire les besoins en eau. Trois variétés, appartenant à différents groupes de maturité, ont été retenues afin d’identifier les traits variétaux d’intérêt pour le semis très précoce. Un ensemble d’essais multilocaux, comportant deux modalités de semis avec irrigation, a été réalisé au cours de 5 années culturales (2010−2014). Le rendement et les besoins en eau ont été déterminés; un suivi dynamique du développement et de la croissance a été réalisé pour la variété Santana. Les effets combinés des basses températures et de la photopériode en réponse au semis précoce se traduisent par une production de biomasse aérienne réduite en phase végétative et une augmentation de la durée de remplissage des graines. Les valeurs maximales de rendement sont observées pour le semis très précoce, mais en moyenne le rendement est sensiblement plus faible en semis très précoce (3,7 t/ha vs. 3,9 t/ha). L’irrigation pour conduire les cultures dans des conditions proches de l’ETM a été sensiblement plus faible en semis très précoce (170 mm vs. 182 mm). Une variété tardive (groupe de maturité II) apparaît mieux adaptée au semis très précoce qu’une variété de groupe de maturité I. Cette étude constitue une première référence agronomique d’évaluation du semis très précoce du soja et suggère que des types variétaux très tardifs pourraient améliorer le potentiel de rendement du soja en semis très précoce pour des conduites irriguées dans le Sud-Ouest de la France

Le semis très précoce : une stratégie agronomique pour améliorer les performances du soja en France ?

Le semis très précoce du soja a été étudié dans l’objectif d’améliorer le potentiel de rendement et/ou de réduire les besoins en eau. Trois variétés, appartenant à différents groupes de maturité, ont été retenues afin d’identifier les traits variétaux d’intérêt pour le semis très précoce. Un ensemble d’essais multilocaux, comportant deux modalités de semis avec irrigation, a été réalisé au cours de 5 années culturales (2010-2014). Le rendement et les besoins en eau ont été déterminés; un suivi dynamique du développement et de la croissance a été réalisé pour la variété Santana. Les effets combinés des basses températures et de la photopériode en réponse au semis précoce se traduisent par une production de biomasse aérienne réduite en phase végétative et une augmentation de la durée de remplissage des graines. Les valeurs maximales de rendement sont observées pour le semis très précoce, mais en moyenne le rendement est sensiblement plus faible en semis très précoce (3,7 t/ha vs. 3,9 t/ha). L’irrigation pour conduire les cultures dans des conditions proches de l’ETM a été sensiblement plus faible en semis très précoce (170 mm vs. 182 mm). Une variété tardive (groupe de maturité II) apparaît mieux adaptée au semis très précoce qu’une variété de groupe de maturité I. Cette étude constitue une première référence agronomique d’évaluation du semis très précoce du soja et suggère que des types variétaux très tardifs pourraient améliorer le potentiel de rendement du soja en semis très précoce pour des conduites irriguées dans le Sud-Ouest de la France.This study was carried out on very early sowing of soybean in order to improve potential yield and/or reduce water requirements. Three varieties belonging to different maturity groups were selected to identify varietal traits of interest in very early sowing. A set of multi-location irrigated trials consisting in two sowing dates was performed from 2010 to 2014. Yield and water requirements were determined; crop development and growth was monitored on cv. Santana. The combined effects of low temperatures and photoperiod in very early sowing resulted in limited aboveground biomass production during vegetative period and increased grain filling duration. Maximal values for yield were observed in very early sowing modality, although yield was slightly lower in very early sowing compared to conventional one (3.7 t/ha vs. 3.9 t/ha). The amount of water brought by irrigation for meeting ETM conditions was slightly lower in very early sowing (170 mm vs. 182 mm). A late variety (maturity group II) appears better adapted to very early sowing compared to a maturity group I variety. This study stands as the first agronomical reference for evaluating early sowing of soybean and suggests that late-varietal type could improve soybean potential yield for early sowing in irrigated cropping conditions of South-Western France

Building spaces of interactions between researchers and managers: Case studies with wildlife monitoring and conservation in France

International audience1. To document and halt biodiversity loss, monitoring, quantifying trends and assessing management and conservation strategies on wildlife populations and communities are crucial steps. 2. With increasing technological innovations, more and more data are collected and new quantitative methods are constantly developed. These rapid developments come with an increasing need for analytical skills, which are hardly accessible to managers. On the other hand, researchers spend more and more time on research grant applications and administrative tasks, which leaves fewer opportunities for knowledge transfer. This situation tends to increase the gap between researchers and managers. Here, we illustrate how to fill this gap by presenting two long-term collaborations between a research unit—Centre for Functional and Evolutionary Ecology; CEFE—and a national agency—French Biodiversity Agency; OFB. 3. The first example is a collaboration providing statistical support to national parks for the design and implementation of scientific monitoring protocols. It relies on the recruitment of a research engineer funded by OFB and physically based at CEFE, who works closely with OFB and managers. The second example is a collaboration on the management of large carnivores. For more than 10 years, it has involved several PhD students and post-doctoral fellows co-supervised by CEFE and OFB, and has recently resulted in the recruitment of a permanent OFB researcher who works half-time at CEFE and half-time at OFB. These case studies illustrate the modalities of collaborative work between public institutions acting at different levels of biodiversity conservation for the co-construction of research agendas and the exchange of knowledge. 4. These collaborations also bring out some challenges. Inter-knowledge and mutual learning remain difficult at scales larger than that of the teams concerned. The staff working at this interface needs to possess good listening skills, respect all partners' needs and demonstrate flexibility. Knowledge exchanges require time, thus reducing productivity according to quantitative metrics such as scientific publications or institutional reports. These collaborations can therefore be difficult to assume socially, and remain tenuous because they rely on a good understanding of the differences in governance of the various partners. 5. Based on our experience, success is favoured by long-term and close relationships, and by co-construction of projects at early stage. Sharing a space (i.e. office or building) facilitates face-to- face interactions during planned work sessions and casual meetings that build up a shared scientific culture and mutual trust

Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies