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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
GetOrganelle: a fast and versatile toolkit for accurate de novo assembly of organelle genomes
GetOrganelle is a state-of-the-art toolkit to accurately assemble organelle genomes from whole genome sequencing data. It recruits organelle-associated reads using a modified “baiting and iterative mapping” approach, conducts de novo assembly, filters and disentangles the assembly graph, and produces all possible configurations of circular organelle genomes. For 50 published plant datasets, we are able to reassemble the circular plastomes from 47 datasets using GetOrganelle. GetOrganelle assemblies are more accurate than published and/or NOVOPlasty-reassembled plastomes as assessed by mapping. We also assemble complete mitochondrial genomes using GetOrganelle. GetOrganelle is freely released under a GPL-3 license (
https://github.com/Kinggerm/GetOrganelle
).
Journal Article
The human genome
\"Teens explore the history of the Human Genome Project from a journalistic viewpoint to understand the events that made genome sequencing possible, the people involved, and its impact on the field of medicine\"-- Provided by publisher.
Book
OC48 HBV integration can sustain intrahepatic HDV activity and can modulate HBV pathogenetic potential
BackgroundHDV depends on HBsAg for its infectivity. HBsAg can derive from cccDNA and also from the integration of the so-called linear HBV-DNA in the genome of infected hepatocytes. Here, we elucidate the contribution of HBsAg production from linear HBV-DNA integration in sustaining HDV activity and its pathogenetic potential.Material and Methods70 liver biopsies from eAg-negative individuals (74% NUC-treated) were included: 35 with CHB and 35 with CHD. Droplet-digital PCR was used to quantify intrahepatic levels of cccDNA, pgRNA, HDV-RNA and HBs transcripts from cccDNA and from integrated HBV-DNA (Grudda, 2022). Next-generation sequencing by Illumina was applied to assess the integration of linear HBV-DNA in hepatocytes’ genome (in 22 CHB and 32 CHD).ResultsIndividuals with CHD and CHB had comparable age and NUC-treatment duration. CHD was characterized by lower cccDNA and pgRNA than CHB (median [IQR]: 1 [0.02–12] vs 24 [8–93] copies (cps)/1000 cells and 8 [1–147] vs 518 [57–3,894] cps/1000cells, P<0.0001 for both). In CHD, no correlation was observed between cccDNA and intrahepatic HDV-RNA, supporting that HDV replicative activity is not strictly related to the extent of HBV reservoir.At least 1 event of linear HBV-DNA integration was observed in 100% and 78.1% (25/32) of individuals with CHB and CHD (total number of unique HBV-integration events: 847 in CHB and 427 in CHD). Furthermore, in both CHB and CHD, a comparable production of HBs transcripts was observed, with >99% of them from integrated HBV-DNA (median [IQR] cps/1000cells: 12,776 [4,570–55,977] in CHB and 6,041 [323–29,446] in CHD).Among the 427 HBV-integration events observed in CHD, 180 involved coding regions of the hepatocytes’ genome, corresponding to a median (IQR) number of 5 (2–10) unique events per patient. Notably, the number of HBV-integration events in coding regions showed a positive correlation with the amount of integration-derived HBsAg transcripts and with serum HBsAg (Rho=0.54 and 0.64, P<0.01 for both). Even more, HBV-integration events were significantly more frequent in individuals with CHD characterized by higher serum HBsAg levels (median [IQR] number of unique HBV-integration events: 10 [7–16] in people with vs 2 [1–7] in people without serum HBsAg >4 logIU/ml; P=0.01).In 19/25 individuals with CHD characterized by >1 HBV-integration event, HBV-DNA integrants localised in human genes regulating cell proliferation. Among the 60 genes identified, 40 genes are already known to be specifically involved in hepatocarcinogenesis.ConclusionsHDV persistence is independent from the intrahepatic HBV reservoir and is sustained by HBsAg production from integrated HBV-DNA. Higher HBsAg levels (>4logIU/ml) can reflect an enrichment of HBV-DNA integration events in coding regions of hepatocytes’ genome.Localization of HBV integrants suggests that these events may potentially induce hepatocytes proliferation, paving the way for carcinogenesis.
Journal Article
Neanderthal man : in search of lost genomes
\"What can we learn from the genes of our closest evolutionary relatives? Neanderthal Man tells the story of geneticist Svante Pääbo's mission to answer that question, beginning with the study of DNA in Egyptian mummies in the early 1980s and culminating in his sequencing of the Neanderthal genome in 2009. From Pääbo, we learn how Neanderthal genes offer a unique window into the lives of our hominin relatives and may hold the key to unlocking the mystery of why humans survived while Neanderthals went extinct. Drawing on genetic and fossil clues, Pääbo explores what is known about the origin of modern humans and their relationship to the Neanderthals and describes the fierce debate surrounding the nature of the two species' interactions. A riveting story about a visionary researcher and the nature of scientific inquiry, Neanderthal Man offers rich insight into the fundamental question of who we are\"-- Provided by publisher.
Book
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