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100 ideas that changed the web
This innovative title looks at the history of the Web from its early roots in the research projects of the US government to the interactive online world we know and use today. Fully illustrated with images of early computing equipment and the inside story of the online world's movers and shakers, the book explains the origins of the Web's key technologies, such as hypertext and mark-up language, the social ideas that underlie its networks, such as open source, and creative commons, and key moments in its development, such as the movement to broadband and the Dotcom Crash. Later ideas look at the origins of social networking and the latest developments on the Web, such as The Cloud and the Semantic Web. Following the design of the previous titles in the series, this book will be in a new, smaller format. It provides an informed and fascinating illustrated history of our most used and fastest-developing technology.
Book
Genetic studies of body mass index yield new insights for obesity biology
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (
P
< 5 × 10
−8
), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.
Genetic correlates of obesity
In the second of two Articles in this issue from the GIANT Consortium, Elizabeth Speliotes and collegues conducted a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), commonly used to define obesity and assess adiposity, to find 97 BMI-associated loci, of which 56 were novel. Many of these loci have significant effects on other metabolic phenotypes. The 97 loci account for about 2.7% of BMI variation, and genome-wide estimates suggest common variation accounts for more than 20% of BMI variation. Pathway analyses implicate the central nervous system in obesity susceptibility including synaptic function, glutamate signaling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Journal Article
The power of genetic diversity in genome-wide association studies of lipids
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use
1
. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels
2
, heart disease remains the leading cause of death worldwide
3
. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS
4
–
23
have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns
24
. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine
25
, we anticipate that increased diversity of participants will lead to more accurate and equitable
26
application of polygenic scores in clinical practice.
A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.
Journal Article
Multi-ethnic genome-wide association study for atrial fibrillation
Atrial fibrillation (AF) affects more than 33 million individuals worldwide
1
and has a complex heritability
2
. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
This large, multi-ethnic genome-wide association study identifies 97 loci significantly associated with atrial fibrillation. These loci are enriched for genes involved in cardiac development, electrophysiology, structure and contractile function.
Journal Article
The Web was done by amateurs : a reflection on one of the largest collective systems ever engineered
\"This book stems from the desire to systematize and put down on paper essential historical facts about the Web, a system that has undoubtedly changed our lives in just a few decades. But how did it manage to become such a central pillar of modern society, such an indispensable component of our economic and social interactions? How did it evolve from its roots to today? Which competitors, if any, did it have to beat out? Who are the heroes behind its success? /These are the sort of questions that the book addresses. Divided into four parts, it follows and critically reflects on the Web's historical path. \"Part I: The Origins\" covers the prehistory of the Web. It examines the technology that predated the Web and fostered its birth. In turn, \"Part II: The Web\" describes the original Web proposal as defined in 1989 by Tim Berners-Lee and the most relevant technologies associated with it. \"Part III: The Patches\" combines a historical reconstruction of the Web's evolution with a more critical analysis of its original definition and the necessary changes made to the initial design. In closing, \"Part IV: System Engineering\" approaches the Web as an engineered infrastructure and reflects on its technical and societal success. The book is unique in its approach, combining historical facts with the technological evolution of the Web. It was written with a technologically engaged and knowledge-thirsty readership in mind, ranging from curious daily Web users to undergraduate computer science and engineering students.\"--Back cover.
Book
Genetic diversity fuels gene discovery for tobacco and alcohol use
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury
1
–
4
. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries
5
. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
A multi-ancestry meta-regression study analyses diverse genome-wide association studies and genome loci associated with tobacco and alcohol use.
Journal Article
A genome-wide association study of anorexia nervosa
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for
in silico
(two data sets) or
de novo
(13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge–purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (
P
=3.01 × 10
−7
) in
SOX2OT
and rs17030795 (
P
=5.84 × 10
−6
) in
PPP3CA
. Two additional signals were specific to Europeans: rs1523921 (
P
=5.76 × 10
−
6
) between
CUL3
and
FAM124B
and rs1886797 (
P
=8.05 × 10
−
6
) near
SPATA13
. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (
P
=4 × 10
−6
), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
Journal Article