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Träfflista för sökning "WFRF:(Esko Tõnu) srt2:(2019)"

Sökning: WFRF:(Esko Tõnu) > (2019)

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1.
  • Justice, Anne E., et al. (författare)
  • Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
  • 2019
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF &gt;= 5%) and nine low-frequency or rare (MAF &lt; 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.</p>
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2.
  • Karlsson Linnér, Richard, et al. (författare)
  • Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences
  • 2019
  • Ingår i: Nature genetics. - 1546-1718. ; 51:2, s. 245-
  • Tidskriftsartikel (refereegranskat)abstract
    • Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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3.
  • Njølstad, Pål Rasmus, et al. (författare)
  • Roadmap for a precision-medicine initiative in the Nordic region
  • 2019
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036.
  • Tidskriftsartikel (refereegranskat)abstract
    • The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.
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4.
  • Bentley, Amy R., et al. (författare)
  • Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids
  • 2019
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:4, s. 636-
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.</p>
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5.
  • de Vries, Paul S., et al. (författare)
  • Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
  • 2019
  • Ingår i: American Journal of Epidemiology. - Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P &lt; 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P &lt; 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.</p>
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6.
  • Kilpelainen, Tuomas O., et al. (författare)
  • Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
  • 2019
  • Ingår i: Nature Communications. - London : Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol- increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.</p>
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7.
  • Njølstad, Pål Rasmus, et al. (författare)
  • Roadmap for a precision-medicine initiative in the Nordic region
  • 2019
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:6, s. 924-930
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • <p>The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.</p>
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8.
  • Stahl, Eli A., et al. (författare)
  • Genome-wide association study identifies 30 loci associated with bipolar disorder
  • 2019
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 51:5, s. 793-803
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P &lt; 1 × 10<sup>-4</sup> in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P &lt; 5 × 10<sup>-8</sup>) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.</p>
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9.
  • Stahl, Eli A, et al. (författare)
  • Genome-wide association study identifies 30 loci associated with bipolar disorder
  • 2019
  • Ingår i: Nature genetics. - 1546-1718. ; 51:5, s. 793-
  • Tidskriftsartikel (refereegranskat)abstract
    • Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
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10.
  • Sung, Yun Ju, et al. (författare)
  • A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
  • 2019
  • Ingår i: Human Molecular Genetics. - Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (<em>P</em> &lt; 5 × 10<sup>−8</sup>, false discovery rate &lt; 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include <em>CSMD1</em> previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. <em>SLC26A7</em> encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. <em>AVPR1A</em> is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. <em>FHAD1</em> is a long non-coding RNA overexpressed in heart failure. <em>TMEM51</em> was associated with contractile function in cardiomyocytes. <em>CASP9</em> plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.</p>
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