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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Rethinking the fall of the planter class

This issue of Atlantic Studies began life as a one-day conference held at Chawton House Library in Hampshire, UK, and funded by the University of Southampton. The conference aimed, like this issue, to bring together scholars currently working on the history of the British West Indian planter class in the eighteenth and nineteenth centuries and to discuss how, when, and why the fortunes of the planters went into decline. As this introduction notes, the difficulties faced by the planter class in the British West Indies from the 1780s onwards were an early episode in a wider drama of decline for New World plantation economies. The American historian Lowell Ragatz published the first detailed historical account of their fall. His work helped to inform the influential arguments of Eric Williams, which were later challenged by Seymour Drescher. Recent research has begun to offer fresh perspectives on the debate about the decline of the planters, and this collection brings together articles taking a variety of new approaches to the topic, encompassing economic, political, cultural, and social histor

Quantitative Trait Nucleotide Analysis Using Bayesian Model Selection

Although much attention has been given to statistical genetic methods for the initial localization and fine mapping of quantitative trait loci (QTLs), little methodological work has been done to date on the problem of statistically identifying the most likely functional polymorphisms using sequence data. In this paper we provide a general statistical genetic framework, called Bayesian quantitative trait nucleotide (BQTN) analysis, for assessing the likely functional status of genetic variants. The approach requires the initial enumeration of all genetic variants in a set of resequenced individuals. These polymorphisms are then typed in a large number of individuals (potentially in families), and marker variation is related to quantitative phenotypic variation using Bayesian model selection and averaging. For each sequence variant a posterior probability of effect is obtained and can be used to prioritize additional molecular functional experiments. An example of this quantitative nucleotide analysis is provided using the GAW12 simulated data. The results show that the BQTN method may be useful for choosing the most likely functional variants within a gene (or set of genes). We also include instructions on how to use our computer program, SOLAR, for association analysis and BQTN analysis

Targeting heat shock proteins in colorectal cancer

Colorectal cancer (CRC) causes over half a million deaths worldwide and has a particularly poor prognosis when diagnosed at an advanced stage. Heat shock proteins (HSP) have been found to be elevated in CRC patients and HSPB1, HSPA1A and HSPC1 has been shown to have some prognostic value. CRC, in common with all cancers, has important associated oncogene and tumor suppressor gene associations and we show how many of these interact directly with one or more of the HSP. We discuss the current chemotherapeutic options available to the clinician when presented with CRC and how these may be improved with a consideration of the role of HSP in the development of the tumor as well as the response to therapy. Direct manipulation of HSP has the potential to decrease the therapeutic dose of anti-tumor drugs and we propose novel strategies that have the potential to be adapted to the clinic

Primary colorectal cells culture as a translational research model

Preclinical studies are an essential stage for any pharmacological agent hoping to make its way into clinical trials. An ideal preclinical model that can accurately predict clinical response does not exist and the best that the scientific community have at the moment is to select the most relevant study model pertaining to the disease of interest from those available, which includes: cell lines, animal models, and even in-silico methodology. Currently, there is a huge gap between preclinical and clinical trial results, indicating that there is much room for improvement in developing a better model to bridge the translational gap.</p

Preseli dolerite bluestones: axe-heads, Stonehenge monoliths and outcrop sources

Chemical compositions and magnetic susceptibility data were compared for 12 dolerite bluestone implements including axes, axe-hammers and battle-axes, 11 Stonehenge monoliths (chemical data only), and potential source outcrops in Preseli, South Wales. Most of the studied artefacts are of spotted dolerite, a small number being unspotted dolerite. Bivariate graphs, discriminant analysis and t-tests were used singly and in combination to show, respectively, that the implements found at sites in England are mainly similar to Stonehenge monoliths, while the implements found in Wales have a variety of compositions and are much less similar to Stonehenge monoliths. The dichotomy between English and Welsh dolerite bluestone implements could be explained by exploitation of different Preseli outcrops or erratic assemblages derived from them. A small number of spotted dolerite implements have previously been shown to have chemical compositions atypical of and marginal to Preseli, suggesting the possibility of a source of spotted dolerite outside Preseli. Previously published analytical data in combination with the new implement/outcrop comparisons presented in this paper support derivation of the majority of analysed Stonehenge monoliths at one particular outcrop within the group of four identified by Thorpe et al. 15 years ago. Analysis of all the extant bluestone monoliths at Stonehenge (now possible using non-destructive methods) would allow progress in identifying monolith outcrop sources, and in understanding the links with the bluestone axe trade