Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Limits to reproduction and seed size-number tradeoffs that shape forest dominance and future recovery

The relationships that control seed production in trees are fundamental to understanding the evolution of forest species and their capacity to recover from increasing losses to drought, fire, and harvest. A synthesis of fecundity data from 714 species worldwide allowed us to examine hypotheses that are central to quantifying reproduction, a foundation for assessing fitness in forest trees. Four major findings emerged. First, seed production is not constrained by a strict trade-off between seed size and numbers. Instead, seed numbers vary over ten orders of magnitude, with species that invest in large seeds producing more seeds than expected from the 1:1 trade-off. Second, gymnosperms have lower seed production than angiosperms, potentially due to their extra investments in protective woody cones. Third, nutrient-demanding species, indicated by high foliar phosphorus concentrations, have low seed production. Finally, sensitivity of individual species to soil fertility varies widely, limiting the response of community seed production to fertility gradients. In combination, these findings can inform models of forest response that need to incorporate reproductive potential

Limits to reproduction and seed size-number trade-offs that shape forest dominance and future recovery

International audienceThe relationships that control seed production in trees are fundamental to understanding the evolution of forest species and their capacity to recover from increasing losses to drought, fire, and harvest. A synthesis of fecundity data from 714 species worldwide allowed us to examine hypotheses that are central to quantifying reproduction, a foundation for assessing fitness in forest trees. Four major findings emerged. First, seed production is not constrained by a strict trade-off between seed size and numbers. Instead, seed numbers vary over ten orders of magnitude, with species that invest in large seeds producing more seeds than expected from the 1:1 trade-off. Second, gymnosperms have lower seed production than angiosperms, potentially due to their extra investments in protective woody cones. Third, nutrient-demanding species, indicated by high foliar phosphorus concentrations, have low seed production. Finally, sensitivity of individual species to soil fertility varies widely, limiting the response of community seed production to fertility gradients. In combination, these findings can inform models of forest response that need to incorporate reproductive potential

Spatial and temporal ecology of oak toads (Bufo quercicus) on a Florida landscape.

ABSTRACT: We used data from 10 years of continuous, concurrent monitoring of oak toads at eight isolated, ephemeral ponds in Florida longleaf pine-wiregrass uplands to address: (1) did weather variables affect movement patterns of oak toads?; (2) did pond hydrology and the condition of surrounding uplands affect pond selection by adults or juvenile recruitment?; (3) were population trends evident?; and (4) did a classical metapopulation model best represent their population ecology? Of 4076 oak toads captured, 92.2% were adults. Substantial (n _ 30 exiting juveniles) recruitment occurred only three times (once each at three ponds during two years). Males outnumbered females (average for all years 2.3:1). Most captures occurred during May–September. Adult captures during June–August increased with heavier rainfall but were not influenced by the durations of preceding dry periods. Movement patterns of metamorphs suggested that oak toads emigrated when moisture conditions become favorable. Pond use by adults was correlated with maximum change in pond depth (May–September). Juvenile recruitment was negatively correlated with minimum pond depth and the number of weeks since a pond was last dry, and positively correlated with the maximum number of weeks a pond held water continuously. The number of breeding adults and juvenile recruitment were highest at ponds within the hardwood-invaded upland matrix. The direction of most immigrations and emigrations was nonrandom, but movement occurred from all directions, and the mean direction of pond entry and exit did not always correspond. A total of 21.1% of individuals was recaptured; 13.3% of first captures were recaptured during the same year, and 7.7% during a subsequent year. Only 1.9% of captured oak toads moved among ponds, mostly within a distance of 132 m. We did not detect adult population trends over the 10- yr studied. Presence or absence at ponds in any given year was a poor indicator of overall use. We saw little evidence of local extinction or ‘‘rescue,’’ but were unable to determine whether juveniles returned to natal ponds or colonized new ponds for breeding as adults. Oak toad conservation can best be ensured by maintaining multiple ponds within a landscape to increase the probability of recruitment within the landscape neighborhood during at least some years and at some ponds, and to increase the likelihood of interpond movement

Long-term monitoring of fleshy fruit and hard mast production and seasonal bird distribution at the Savannah River Site, South Carolina.

A final report of Fruit and hard mast production in five habitat types at SRS with a comparison of fruit consumption by fledgling versus adult birds at SRS and Relative importance of fruit, seeds, and insects in the diets of overwintering birds at SRS

Projected Climate and Hydroregime Variability Constrain Ephemeral Wetland-Dependent Amphibian Populations in Simulations of Southern Toads

Amphibian populations are threatened globally by stressors, including diminishing availability of suitable wetland breeding sites, altered hydroregimes driven by changing weather patterns, and exposure to contaminants. Ecological risk assessment should encompass spatial and temporal scales that capture influential ecological processes and demographic responses. Following the PopGUIDE framework of population model development for risk assessment, we used matrix population models, in conjunction with existing hydroregime predictions, under a climate change scenario to evaluate the effects of environmental stochasticity and aquatic pesticide exposure on amphibians that are dependent on ephemeral wetlands. Using southern toads (Anaxyrus terrestris) as an example, we simulated population dynamics with breeding success dependent on hydroregime suitability. Years were defined as optimal, marginal, or insufficient for successful toad recruitment, based on the duration of their potential breeding season and rate of larval development to metamorphosis. We simulated both probabilistic and chronologically specific population projections, including variable annual fecundity, based on hydroregime suitability and reduced larval survival from carbaryl exposure. In our simulations, populations were more negatively impacted by prolonged drought, and consequently multiple sequential years of reproductive failure, than by aquatic pesticide exposure. These results highlight the necessity of reliable climate projections to accurately represent the effects of altered hydroregimes on amphibian populations. Risk assessment approaches could be improved with flexible modifications that allow inclusion of various extrinsic stressors and identification of demographic and ecological vulnerabilities when precise data are lacking

Home range and activity patterns by gray foxes, Urocyon cinereoargenteus (Carnivora: Canidae), in east Tennessee

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