Showing papers by "Terho Lehtimäki published in 2021"
Bin Zhou1, Rodrigo M. Carrillo-Larco1, Goodarz Danaei2, Leanne M. Riley2 +1141 more•Institutions (5)
TL;DR: In this article, a Bayesian hierarchical model was used to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control).
918 citations
University Medical Center Groningen1, Netherlands Cancer Institute2, European Bioinformatics Institute3, Georgia Institute of Technology4, Leipzig University5, Johns Hopkins University6, NHS Blood and Transplant7, University of Cambridge8, Garvan Institute of Medical Research9, University of Tartu10, Ontario Institute for Cancer Research11, University of Washington12, Public Health Research Institute13, University of Chicago14, Greifswald University Hospital15, Ludwig Maximilian University of Munich16, University of Bristol17, Erasmus University Rotterdam18, Royal Devon and Exeter Hospital19, Luleå University of Technology20, University of Westminster21, Swiss Institute of Bioinformatics22, University of Lausanne23, University of Geneva24, University of Dundee25, Agency for Science, Technology and Research26, University of Queensland27, Leiden University Medical Center28, Radboud University Nijmegen29, University of Liège30, University of Oxford31, Menzies Research Institute32, Icahn School of Medicine at Mount Sinai33, Ikerbasque34, VU University Amsterdam35, Stanford University36, Turku University Hospital37, University of Turku38, Maastricht University39, Karolinska Institutet40, Utrecht University41, University of Helsinki42, National Institutes of Health43, Technische Universität München44, Wellcome Trust Sanger Institute45, German Cancer Research Center46, Westlake University47, University of New South Wales48
TL;DR: In this article, the authors performed cis-and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium.
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
344 citations
Maria Lc Iurilli1, Bin Zhou1, James E. Bennett1, Rodrigo M. Carrillo-Larco1 +1399 more•Institutions (374)
TL;DR: In this article, the authors investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants.
Abstract: From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.
81 citations
University of Southern California1, University of Bordeaux2, University of Washington3, United States Department of Veterans Affairs4, Kaiser Permanente5, University of California, Irvine6, University of California, Los Angeles7, Cleveland Clinic8, Emory University9, Leipzig University10, Heidelberg University11, Medical University of Graz12, Augsburg College13, University College London14, Utrecht University15, St Bartholomew's Hospital16, University of Tampere17, National University of Singapore18, University Health System19, Duke University20, Vanderbilt University Medical Center21, Columbia University22, University of Tokyo23, Kyoto University24, University of Arizona25, University of Virginia26, Icahn School of Medicine at Mount Sinai27, Karolinska University Hospital28
TL;DR: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques and thrombus formation as mentioned in this paper.
Abstract: Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000) Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI Confirmatory evidence for association of a locus on chromosome 1p213 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000) Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p213, increased in ischaemic (vs non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs vehicle), and associated with smooth muscle cell migration in vitro Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques
64 citations
University of Granada1, Washington University in St. Louis2, University of Helsinki3, Martin Luther University of Halle-Wittenberg4, Seoul National University5, University of Oulu6, University of Gothenburg7, Ludwig Maximilian University of Munich8, University of Tampere9, University of Texas at Austin10, University of Turku11, Turku University Hospital12, University of Maryland, Baltimore13
TL;DR: In three large independent genome-wide association studies from Finland, Germany, and Korea, a data-driven machine learning method is used to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated.
Abstract: Phylogenetic, developmental, and brain-imaging studies suggest that human personality is the integrated expression of three major systems of learning and memory that regulate (1) associative conditioning, (2) intentionality, and (3) self-awareness. We have uncovered largely disjoint sets of genes regulating these dissociable learning processes in different clusters of people with (1) unregulated temperament profiles (i.e., associatively conditioned habits and emotional reactivity), (2) organized character profiles (i.e., intentional self-control of emotional conflicts and goals), and (3) creative character profiles (i.e., self-aware appraisal of values and theories), respectively. However, little is known about how these temperament and character components of personality are jointly organized and develop in an integrated manner. In three large independent genome-wide association studies from Finland, Germany, and Korea, we used a data-driven machine learning method to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated. We found three clusters of similar numbers of people with distinct combinations of temperament and character profiles. Their associated genetic and environmental networks were largely disjoint, and differentially related to distinct forms of learning and memory. Of the 972 genes that mapped to the three phenotypic networks, 72% were unique to a single network. The findings in the Finnish discovery sample were blindly and independently replicated in samples of Germans and Koreans. We conclude that temperament and character are integrated within three disjoint networks that regulate healthy longevity and dissociable systems of learning and memory by nearly disjoint sets of genetic and environmental influences.
57 citations
University of Edinburgh1, University of Bristol2, University of California, Los Angeles3, Erasmus University Rotterdam4, Los Angeles Biomedical Research Institute5, University of Basel6, Swiss Tropical and Public Health Institute7, National Institutes of Health8, University of Tartu9, Emory University10, Technische Universität München11, Odense University Hospital12, University of Southern Denmark13, University of Helsinki14, University of Alabama at Birmingham15, University of North Carolina at Chapel Hill16, University of Michigan17, Imperial College London18, Peking University19, Memorial Hospital of South Bend20, Chang Gung University21, King's College London22, Public Health Research Institute23, VU University Amsterdam24, Cancer Council Victoria25, Karolinska Institutet26, University of Texas Health Science Center at Houston27, University of Mississippi Medical Center28, University of Melbourne29, Monash University, Clayton campus30, University of Vermont31, University of Tampere32, Boston University33, Guy's and St Thomas' NHS Foundation Trust34, National Health Service35, University of Minnesota36, University of Turku37, Turku University Hospital38, University of Virginia39, University of Jyväskylä40, University of Mainz41, Ludwig Maximilian University of Munich42, University of Southern California43, Beth Israel Deaconess Medical Center44, Hacettepe University45, University of Kentucky46, Tulane University47, University of Washington48
TL;DR: In this article, the authors identify 137 genome-wide significant loci, of which 113 are novel, from genomewide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels.
Abstract: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
57 citations
TL;DR: The identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
37 citations
University of Helsinki1, University of Toronto2, QIMR Berghofer Medical Research Institute3, Broad Institute4, Washington University in St. Louis5, University of Tampere6, University of Turku7, Turku University Hospital8, National Institutes of Health9, Indiana University10, Centre for Addiction and Mental Health11, University of Southern California12
TL;DR: The authors performed the largest genome-wide association study (GWAS) to date of the nicotine metabolite ratio (NMR) in European ancestry current smokers (n = 5185), found 1255 genomewide significant variants, and replicated the chromosome 19 locus.
Abstract: Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3 ' hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained similar to 38% of NMR variation, a substantial increase from the similar to 20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3 ' hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.
35 citations
TL;DR: The authors found that modern humans have more than 200 unique non-protein coding genes regulating co-expression of many more protein-coding genes in coordinated networks that underlie their capacities for self-awareness, creativity, prosocial behavior, and healthy longevity, which are not found in chimpanzees or Neanderthals.
Abstract: The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and chimpanzees in their numbers of genes for both self-control and self-awareness. 95% of the 267 genes we found only in modern humans were not protein-coding, including many long-non-coding RNAs in the self-awareness network. These genes may have arisen by positive selection for the characteristics of human well-being and behavioral modernity, including creativity, prosocial behavior, and healthy longevity. The genes that cluster in association with those found only in modern humans are over-expressed in brain regions involved in human self-awareness and creativity, including late-myelinating and phylogenetically recent regions of neocortex for autobiographical memory in frontal, parietal, and temporal regions, as well as related components of cortico-thalamo-ponto-cerebellar-cortical and cortico-striato-cortical loops. We conclude that modern humans have more than 200 unique non-protein-coding genes regulating co-expression of many more protein-coding genes in coordinated networks that underlie their capacities for self-awareness, creativity, prosocial behavior, and healthy longevity, which are not found in chimpanzees or Neanderthals.
26 citations
Imperial College London1, Oulu University Hospital2, North-West University3, Technische Universität München4, University of Turku5, Turku University Hospital6, Nanyang Technological University7, University of Düsseldorf8, University of Mainz9, Ludwig Maximilian University of Munich10, University of Oulu11
TL;DR: In this article, an epigenome-wide association study (EWAS) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins, has been presented, which provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses.
Abstract: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
25 citations
TL;DR: In this paper, a genome-wide association meta-analysis (GWAMA) of childhood aggressive behavior (AGG) has been presented, in which all phenotype measures across childhood ages from multiple assessors were included.
Abstract: Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
TL;DR: In this paper, the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways were simultaneously evaluated and the potential mediating effects of these circulating metabolites on the risk of coronary artery disease in adulthood using a sample of 60,801 cases and 123,504 controls.
Abstract: BACKGROUND Individuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways. METHODS Two-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls. RESULTS Univariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P < 4.07 × 10-4). However, the majority of these effects (35/42) substantially attenuated when accounting for adult body size using multivariable MR. We found little evidence that the biomarkers that were potentially influenced directly by childhood body size (leucine, isoleucine and tyrosine) mediate this effect onto adult disease risk. Very-low-density lipoprotein markers provided the strongest evidence of mediating the long-term effect of adiposity on CAD risk. CONCLUSIONS Our findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.
Lisa de las Fuentes1, Yun Ju Sung1, Raymond Noordam2, Thomas W. Winkler3 +240 more•Institutions (81)
TL;DR: A role of educational attainment or SES in further dissection of the genetic architecture of BP is suggested and several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation.
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 x 10(-8)). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Tarunveer S. Ahluwalia1, Tarunveer S. Ahluwalia2, Bram P. Prins3, Mohammadreza Abdollahi3 +150 more•Institutions (58)
TL;DR: This article conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67,428 individuals of European ancestry.
Abstract: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Baker IDI Heart and Diabetes Institute1, University of Oulu2, University of Cambridge3, University of Turku4, Turku University Hospital5, University of Tampere6, National Institutes of Health7, University of Helsinki8, University of Tartu9, National Institute for Health Research10, University of Eastern Finland11
TL;DR: This work was supported by Academy of Finland, Finnish Cardiovascular Research, Juho Vainio, Paavo Nurmi, Finnish Cultural, Tampere Tuberculosis, Emil Aaltonen, Yrjo Jahnsson, Signe and Ane Gyllenberg, and Finnish Diabetes Research.
Abstract: Aims Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement. Methods and results Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function. Conclusions Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.
Erasmus University Rotterdam1, University of Jyväskylä2, UCL Institute of Ophthalmology3, University of Helsinki4, Moorfields Eye Hospital5, King's College London6, National Research Council7, Sun Yat-sen University8, University of Tampere9, University of Turku10, Turku University Hospital11, National University of Singapore12, Capital Medical University13, Heidelberg University14, University of Wisconsin-Madison15, National Institutes of Health16, UCL Institute of Child Health17, University of Bristol18, University of Melbourne19, University of Western Australia20, Cardiff University21
TL;DR: In this article, the same authors assess whether a common set of genetic variants are associated with susceptibility to low myopia (LM) and high myopia and hyperopia and find that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM and that individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles compared with individuals with LM.
Abstract: Importance Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. Objective To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. Design, Setting, and Participants This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. Exposures Four refractive error groups were defined: HM, −6.00 diopters (D) or less; LM, −3.00 to −1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. Main Outcomes and Measures Odds ratios (ORs) of polygenic risk scores in replication samples. Results A total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77;P = 1.54 × 10−15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23;P = 8.14 × 10−5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89;P = 4.18 × 10−7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59;P = 1.43 × 10−16). Conclusions and Relevance Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.
TL;DR: In this paper, Cardiovascular risk factors, such as high blood pressure, adverse serum lipids, and elevated body mass index in midlife, may harm cognitive performance, and it is important to note that lon...
Abstract: Background: Cardiovascular risk factors, such as high blood pressure, adverse serum lipids, and elevated body mass index in midlife, may harm cognitive performance. It is important to note that lon...
TL;DR: In this article, the role of cytokines as intermediates in the pathway from increased adiposity to disease was investigated, and the impact of BMI-driven cytokines on risk of obesityrelated diseases was investigated.
Abstract: Objective This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease. Methods BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases. Results Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases. Conclusions Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.
TL;DR: The Cardiovascular Risk in Young Finns Study as discussed by the authors, a population-based prospective cohort study that started in 1980 with follow-up over 28 years, was used to identify the relative association of non-HDL-C measured at distinct life stages (adolescence, young adulthood, mid-adulthood) with the presence of coronary artery calcification (CAC), a marker of heart disease in adulthood.
Abstract: Importance Elevated non–high-density lipoprotein cholesterol (non–HDL-C) is associated with the presence of coronary artery calcification (CAC), a marker of heart disease in adulthood. However, the relative importance of non–HDL-C levels at specific life stages for CAC remains unclear. Objective To identify the relative association of non–HDL-C measured at distinct life stages (adolescence, young adulthood, mid-adulthood) with the presence of CAC measured in mid-adulthood. Design, Setting, and Participants The Cardiovascular Risk in Young Finns Study is a population-based prospective cohort study that started in 1980 with follow-up over 28 years. Participants from 3 population centers (Kuopio, Tampere, and Turku in Finland) represent a convenience sample drawn from the 3 oldest cohorts at baseline (aged 12-18 years in 1980). Data were collected from September 1980 to August 2008. Analysis began February 2020. Exposures Non–HDL-C levels were measured at 3 life stages including adolescence (aged 12-18 years), young adulthood (aged 21-30 years), and mid-adulthood (aged 33-45 years). Main Outcomes and Measures In 2008, CAC was determined from computed tomography and dichotomized as 0 (no CAC, Agatston score = 0) and 1 (presence of CAC, Agatston score ≥1) for analysis. Using a bayesian relevant life course exposure model, the relative association was determined between non–HDL-C at each life stage and the presence of CAC in mid-adulthood. Results Of 589 participants, 327 (56%) were female. In a model adjusted for year of birth, sex, body mass index, systolic blood pressure, blood glucose level, smoking status, lipid-lowering and antihypertensive medication use, and family history of heart disease, cumulative exposure to non–HDL-C across all life stages was associated with CAC (odds ratio [OR], 1.50; 95% credible interval [CrI], 1.14-1.92). At each life stage, non–HDL-C was associated with CAC and exposure to non–HDL-C during adolescence had the strongest association (adolescence: OR, 1.16; 95% CrI, 1.01-1.46; young adulthood: OR, 1.14; 95% CrI, 1.01-1.43; mid-adulthood: OR, 1.12; 95% CrI, 1.01-1.34). Conclusions and Relevance These data suggest that elevated non–HDL-C levels at all life stages are associated with coronary atherosclerosis in mid-adulthood. However, adolescent non–HDL-C levels showed the strongest association with the presence of CAC in mid-adulthood, and greater awareness of the importance of elevated non–HDL-C in adolescence is needed.
University of Gothenburg1, Minia University2, Odense University Hospital3, University of Southern Denmark4, University of Oulu5, Universidade Federal de Goiás6, University of Ulm7, Australian Catholic University8, Sahlgrenska University Hospital9, University of Tampere10, University of Bristol11, McGill University12
TL;DR: In this article, the fracture reducing allele at the RSPO3 locus associated with increased expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans.
Abstract: With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.
Public Health Research Institute1, University of Bristol2, Leiden University Medical Center3, Duke University4, Goethe University Frankfurt5, University of Helsinki6, Leiden University7, Erasmus University Rotterdam8, University of Edinburgh9, University of Turku10, University Medical Center Groningen11, Health Science University12, Pompeu Fabra University13, University of Groningen14, Radboud University Nijmegen15, VU University Amsterdam16, University of Oulu17, Queen's University Belfast18, Heidelberg University19, Karolinska Institutet20, Ghent University21, University of Otago22, University of Exeter23, King's College London24, Max Planck Society25, Emory University26, Vytautas Magnus University27, Norwegian Institute of Public Health28, University of Crete29, Utrecht University30, Maastricht University31, Oslo University Hospital32, Allen Institute for Brain Science33, RWTH Aachen University34, Turku University Hospital35, Helsinki University Central Hospital36, Harvard University37, University of London38, Imperial College London39
TL;DR: The first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants) was reported in this paper. But no epigenomewide significant sites were found.
Abstract: DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
TL;DR: Inverted T waves in the electrocardiogram (ECG) have been associated with coronary heart disease (CHD) and mortality and the pathophysiology and prognostic significance may differ between different anatomical lead groups.
Abstract: Background Inverted T waves in the electrocardiogram (ECG) have been associated with coronary heart disease (CHD) and mortality. The pathophysiology and prognostic significance of T-wave inversion may differ between different anatomical lead groups, but scientific data related to this issue is scarce. Methods A representative sample of Finnish subjects (n = 6,354) aged over 30 years underwent a health examination including a 12-lead ECG in the Health 2000 survey. ECGs with T-wave inversions were divided into three anatomical lead groups (anterior, lateral, and inferior) and were compared to ECGs with no pathological T-wave inversions in multivariable-adjusted Fine-Gray and Cox regression hazard models using CHD and mortality as endpoints. Results The follow-up for both CHD and mortality lasted approximately fifteen years (median value with interquartile ranges between 14.9 and 15.3). In multivariate-adjusted models, anterior and lateral (but not inferior) T-wave inversions associated with increased risk of CHD (HR: 2.37 [95% confidence interval 1.20-4.68] and 1.65 [1.27-2.15], respectively). In multivariable analyses, only lateral T-wave inversions associated with increased risk of mortality in the entire study population (HR 1.51 [1.26-1.81]) as well as among individuals with no CHD at baseline (HR 1.59 [1.29-1.96]). Conclusions The prognostic information of inverted T waves differs between anatomical lead groups. T-wave inversion in the anterior and lateral lead groups is independently associated with the risk of CHD, and lateral T-wave inversion is also associated with increased risk of mortality. Inverted T wave in the inferior lead group proved to be a benign phenomenon.
TL;DR: The work indicates that social and economic factors have a measurable impact on human physiology, and lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts.
Abstract: Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear.
Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in 30 000 adults and 4000 children across 10 UK and Finnish cohort studies.
Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in
small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA),
omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including
levels of their respective lipid constituents) and cholesterol measures across different
density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol
remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP
were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids.
Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally
unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we
found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.
TL;DR: In this article, the authors identified childhood risk factors associated with left ventricular (LV) diastolic function in adulthood, such as obesity, blood pressure, and physical inactivity, in the participants of the Cardiovascular Risk in Young Finns Study.
Abstract: BACKGROUND AND OBJECTIVES: Cardiovascular risk factors, such as obesity, blood pressure, and physical inactivity, have been identified as modifiable determinants of left ventricular (LV) diastolic function in adulthood However, the links between childhood cardiovascular risk factor burden and adulthood LV diastolic function are unknown To address this lack of knowledge, we aimed to identify childhood risk factors associated with LV diastolic function in the participants of the Cardiovascular Risk in Young Finns Study METHODS: Study participants (N = 1871; 459% men; aged 34–49 years) were examined repeatedly between the years 1980 and 2011 We determined the cumulative risk exposure in childhood (age 6–18 years) as the area under the curve for systolic blood pressure, adiposity (defined by using skinfold and waist circumference measurements), physical activity, serum insulin, triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterols Adulthood LV diastolic function was defined by using E/e ratio RESULTS: Elevated systolic blood pressure and increased adiposity in childhood were associated with worse adulthood LV diastolic function, whereas higher physical activity level in childhood was associated with better adulthood LV diastolic function (P CONCLUSIONS: Adiposity status and the level of physical activity in childhood are independently associated with LV diastolic function in adulthood
TL;DR: The SARS-CoV-2 antibodies can be quite reliable detected 2weeks after NAAT positivity and 3 weeks after the symptom onset with both tests, however, since some COVID-19 patients were positive only with Elecsys®, the antibodies should be screened against N-antigen (Elecsys®), and reactive samples confirmed with S antigen (LIAISON®), but the both results should be reported.
TL;DR: In this article, the associations between serum standardized FA percentages and cardiometabolic outcomes were investigated, including prevalent and incident obesity, insulin resistance (HOMA-IR index in the upper quintile), elevated blood pressure (BP; taking medication, or diastolic or systolic BP, and incident nonalcoholic fatty liver.
Abstract: BACKGROUND The links between fatty acids (FAs) and cardiometabolic outcomes are topics of debate. OBJECTIVE Our aim was to investigate the associations between serum standardized FA percentages and cardiometabolic outcomes. METHODS We used cross-sectional (n = 2187-2200 subjects, age 24-39 y, women 54%) and 10-year prospective data (n = 975-1414 subjects) from the Young Finns Study. Outcomes included prevalent and incident obesity, insulin resistance (HOMA-IR index in the upper quintile), elevated blood pressure (BP; taking medication, or diastolic or systolic BP in the upper quintile), and incident nonalcoholic fatty liver. Logistic regression models were used to calculate ORs per SD increase in fatty acids (FAs). The models were adjusted for age and sex, and additionally for other potential confounders. RESULTS Several cross-sectional findings were also statistically significant in prospective models (Bonferroni corrected P < 0.003). In fully-adjusted models for obesity, these consisted of SFAs (OR: 1.28) and MUFAs (OR: 1.38), including palmitoleic (OR: 1.39) and oleic acids (OR: 1.37). Furthermore, PUFAs (OR: 0.70), including linoleic (OR: 0.67) and docosahexaenoic acids (OR: 0.75), were inversely related with obesity, whereas γ-linolenic acid (OR: 1.32) was positively associated with obesity. In age- and sex-adjusted models for insulin resistance, MUFAs (OR: 1.26) and oleic acid (OR: 1.25) were positively, and PUFAs (OR: 0.81), particularly linoleic acid (OR: 0.78), were inversely associated with HOMA-IR. Similarly with elevated BP, palmitic acid (OR: 1.22), MUFAs (OR: 1.28), and oleic acid (OR: 1.28) were positively associated with elevated BP, whereas PUFAs (OR: 0.77), n-6 (omega-6) PUFAs (OR: 0.79), and linoleic acid (OR: 0.77) were inversely associated. In fully-adjusted models for incident fatty liver, the most consistent predictors were high palmitic (OR: 1.61) and low linoleic acid (OR: 0.63) percentages. The n-6/n-3 (omega-3) PUFA ratio was not linked with any adverse outcomes. CONCLUSIONS High serum percentages of total SFAs and MUFAs and low PUFAs, but also several specific FAs, predict future unfavorable cardiometabolic outcomes in Finnish adults.
TL;DR: In this paper, the authors quantified 437 molecular lipid species from the Young Finns Study cohort (aged 30-45 years and 57% women) and performed lipidomewide multivariate analysis of variance (MANOVA) with early markers for both diseases.
TL;DR: In this paper, the authors explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480).
Abstract: Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (n = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.
Broad Institute1, Harvard University2, Leiden University3, Washington University in St. Louis4, University of Regensburg5, University of Pittsburgh6, Carnegie Mellon University7, National Institutes of Health8, Pasteur Institute9, Icahn School of Medicine at Mount Sinai10, University of Copenhagen11, University of Texas Health Science Center at Houston12, University of São Paulo13, University of Washington14, Erasmus University Rotterdam15, Boston University16, Tulane University17, Duke University18, Pennington Biomedical Research Center19, University of Mississippi20, University of North Carolina at Chapel Hill21, University of Eastern Finland22, University of Geneva23, University of Tartu24, Northwestern University25, University of Edinburgh26, University of Groningen27, Queen Mary University of London28, Wake Forest University29, University of Greifswald30, Vanderbilt University31, University of Adelaide32, University of Maryland, Baltimore33, Johns Hopkins University34, Baylor College of Medicine35, University of Minnesota36, Kaiser Permanente37, University of Alabama at Birmingham38, University of California, Los Angeles39, Jackson State University40, University of Virginia41, Columbia University42, George Washington University43, University of Iowa44, United States Department of Veterans Affairs45, VU University Amsterdam46, Ludwig Maximilian University of Munich47, University of Mainz48, Flinders University49, Sir Charles Gairdner Hospital50, University of Iceland51, University of Oxford52, Fred Hutchinson Cancer Research Center53, Case Western Reserve University54, University of Southern California55
TL;DR: In this article, the authors performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects.
Abstract: Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P-joint < 5 x 10(-8)), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P-int < 5 x 10(-8)). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P-int = 2 x 10(-6)). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P-int < 10(-3)). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
TL;DR: Exposure to parental smoking in childhood was associated with increased risk of overweight/obesity, central obesity and adiposity measured by skinfold thickness from childhood to adulthood.
Abstract: To evaluate the association between childhood parental smoking exposure and the risk of overweight/obesity from childhood to adulthood. This study leverages the data from two longitudinal populatio...