For most Americans, the savings and loan industry is defined by the fraud, ineptitude and failures of the 1980s. However, these events overshadow a long history in which thrifts played a key role in ...helping thousands of households buy homes. First appearing in the 1830s savings and loans, then known as building and loans, encourage their working-class members to adhere to the principles of thrift and mutual co-operation as a way to achieve the 'American Dream' of home ownership. This book traces the development of this industry from its origins as a movement of a loosely affiliated collection of institutions into a major element of America's financial markets. It also analyses how diverse groups of Americans, including women, ethnic Americans and African Americans, used thrifts to improve their lives and elevate their positions in society. Finally the overall historical perspective sheds new light on the events of the 1980s and analyses the efforts to rehabilitate the industry in the 1990s.
Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10
) at the time of this analysis, but a much larger number of ...putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n
= 10,801) as well as a stricter definition without angina (HARD; n
= 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.
We introduce multi-trait analysis of GWAS (MTAG), a method for joint analysis of summary statistics from genome-wide association studies (GWAS) of different traits, possibly from overlapping samples. ...We apply MTAG to summary statistics for depressive symptoms (N
= 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). As compared to the 32, 9, and 13 genome-wide significant loci identified in the single-trait GWAS (most of which are themselves novel), MTAG increases the number of associated loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yield more informative bioinformatics analyses and increase the variance explained by polygenic scores by approximately 25%, matching theoretical expectations.
Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing ...estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual-level genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique-cross-trait LD Score regression-for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity, and educational attainment and several diseases. These results highlight the power of genome-wide analyses, as there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment.
Life in crisis Redfield, Peter
2013., 20130126, 2013, 2013-02-25
eBook
Life in Crisis tells the story of Médecins Sans Frontières (Doctors Without Borders or MSF) and its effort to "save lives" on a global scale. Begun in 1971 as a French alternative to the Red Cross, ...the MSF has grown into an international institution with a reputation for outspoken protest as well as technical efficiency. It has also expanded beyond emergency response, providing for a wider range of endeavors, including AIDS care. Yet its seemingly simple ethical goal proves deeply complex in practice. MSF continually faces the problem of defining its own limits. Its minimalist form of care recalls the promise of state welfare, but without political resolution or a sense of well-being beyond health and survival. Lacking utopian certainty, the group struggles when the moral clarity of crisis fades. Nevertheless, it continues to take action and innovate. Its organizational history illustrates both the logic and the tensions of casting humanitarian medicine into a leading role in international affairs.
Summary
With the advent of rapid genotyping and next‐generation sequencing technologies, genome‐wide association study (GWAS) has become a routine strategy for decoding genotype–phenotype ...associations in many species. More than 1000 such studies over the last decade have revealed substantial genotype–phenotype associations in crops and provided unparalleled opportunities to probe functional genomics. Beyond the many ‘hits’ obtained, this review summarizes recent efforts to increase our understanding of the genetic architecture of complex traits by focusing on non‐main effects including epistasis, pleiotropy, and phenotypic plasticity. We also discuss how these achievements and the remaining gaps in our knowledge will guide future studies. Synthetic association is highlighted as leading to false causality, which is prevalent but largely underestimated. Furthermore, validation evidence is appealing for future GWAS, especially in the context of emerging genome‐editing technologies.
Significance Statement
This review summarizes the latest advances in generating an overall view of the genetic architecture associated with crop complex traits, and discusses how these updated insights will guide future studies. A multiple‐causal‐allele hypothesis was formulated to explain the increasingly common artifact/synthetic associations.
Most sequenced genomes are currently stored in strict access-controlled repositories. Free access to these data could improve the power of genome-wide association studies (GWAS) to identify ...disease-causing genetic variants and aid the discovery of new drug targets. However, concerns over genetic data privacy may deter individuals from contributing their genomes to scientific studies and could prevent researchers from sharing data with the scientific community. Although cryptographic techniques for secure data analysis exist, none scales to computationally intensive analyses, such as GWAS. Here we describe a protocol for large-scale genome-wide analysis that facilitates quality control and population stratification correction in 9K, 13K, and 23K individuals while maintaining the confidentiality of underlying genotypes and phenotypes. We show the protocol could feasibly scale to a million individuals. This approach may help to make currently restricted data available to the scientific community and could potentially enable secure genome crowdsourcing, allowing individuals to contribute their genomes to a study without compromising their privacy.
Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate ...genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease.
Estimating the polygenicity (proportion of causally associated single nucleotide polymorphisms (SNPs)) and discoverability (effect size variance) of causal SNPs for human traits is currently of ...considerable interest. SNP-heritability is proportional to the product of these quantities. We present a basic model, using detailed linkage disequilibrium structure from a reference panel of 11 million SNPs, to estimate these quantities from genome-wide association studies (GWAS) summary statistics. We apply the model to diverse phenotypes and validate the implementation with simulations. We find model polygenicities (as a fraction of the reference panel) ranging from ≃ 2 × 10-5 to ≃ 4 × 10-3, with discoverabilities similarly ranging over two orders of magnitude. A power analysis allows us to estimate the proportions of phenotypic variance explained additively by causal SNPs reaching genome-wide significance at current sample sizes, and map out sample sizes required to explain larger portions of additive SNP heritability. The model also allows for estimating residual inflation (or deflation from over-correcting of z-scores), and assessing compatibility of replication and discovery GWAS summary statistics.
This book is the first in a projected series on Evolutionary Cell Biology , the intent of which is to demonstrate the essential role of cellular mechanisms in transforming the genotype into the ...phenotype by transforming gene activity into evolutionary change in morphology. This book — Cells in Evolutionary Biology — evaluates the evolution of cells themselves and the role cells have been viewed to play as agents of change at other levels of biological organization. Chapters explore Darwin’s use of cells in his theory of evolution and how Weismann’s theory of the separation of germ plasm from body cells brought cells to center stage in understanding how acquired changes to cells within generations are not passed on to future generations.
Chapter 7 of this book is freely available as a downloadable Open Access PDF under a Creative Commons Attribution-Non Commercial-No Derivatives 3.0 license. https://s3-us-west-2.amazonaws.com/tandfbis/rt-files/docs/Open+Access+Chapters/9781315155968_oachapter7.pdf
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