Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu CT
PROVIDER: S-EPMC6602949 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals.
Liu Ching-Ti CT Merino Jordi J Rybin Denis D DiCorpo Daniel D Benke Kelly S KS Bragg-Gresham Jennifer L JL Canouil Mickaël M Corre Tanguy T Grallert Harald H Isaacs Aaron A Kutalik Zoltan Z Lahti Jari J Marullo Letizia L Marzi Carola C Rasmussen-Torvik Laura J LJ Rocheleau Ghislain G Rueedi Rico R Scapoli Chiara C Verweij Niek N Vogelzangs Nicole N Willems Sara M SM Yengo Loïc L Bakker Stephan J L SJL Beilby John J Hui Jennie J Kajantie Eero E Müller-Nurasyid Martina M Rathmann Wolfgang W Balkau Beverley B Bergmann Sven S Eriksson Johan G JG Florez Jose C JC Froguel Philippe P Harris Tamara T Hung Joseph J James Alan L AL Kavousi Maryam M Miljkovic Iva I Musk Arthur W AW Palmer Lyle J LJ Peters Annette A Roussel Ronan R van der Harst Pim P van Duijn Cornelia M CM Vollenweider Peter P Barroso Inês I Prokopenko Inga I Dupuis Josée J Meigs James B JB Bouatia-Naji Nabila N
Scientific reports 20190701 1
Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fas ...[more]
Similar Datasets
Project description: Not available
| S-EPMC6946719 | biostudies-literature
Project description:Aims/hypothesisTo test among diabetes-free urban community-dwelling adults the hypothesis that the proportion of African genetic ancestry is positively associated with glycaemia, after accounting for other continental ancestry proportions, BMI and socioeconomic status (SES).MethodsThe Boston Area Community Health cohort is a multi-stage 1:1:1 stratified random sample of self-identified African-American, Hispanic and white adults from three Boston inner city areas. We measured 62 ancestry informative markers, fasting glucose (FG), HbA1c, BMI and SES (income, education, occupation and insurance status) and analysed 1,387 eligible individuals (379 African-American, 411 Hispanic, 597 white) without clinical or biochemical evidence of diabetes. We used three-heritage multinomial linear regression models to test the association of FG or HbA1c with genetic ancestry proportion adjusted for: (1) age and sex; (2) age, sex and BMI; and (3) age, sex, BMI and SES.ResultsMean age- and sex-adjusted FG levels were 5.73 and 5.54 mmol/l among those with 100% African or European ancestry, respectively. Using per cent European ancestry as the referent, each 1% increase in African ancestry proportion was associated with an age- and sex-adjusted FG increase of 0.0019 mmol/l (p = 0.01). In the BMI- and SES-adjusted model the slope was 0.0019 (p = 0.02). Analysis of HbA1c gave similar results.Conclusions/interpretationA greater proportion of African genetic ancestry is independently associated with higher FG levels in a non-diabetic community-based cohort, even accounting for other ancestry proportions, obesity and SES. The results suggest that differences between African-Americans and whites in type 2 diabetes risk may include genetically mediated differences in glucose homeostasis.
| S-EPMC5424892 | biostudies-literature
Project description:Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well-established that both common and rare sequence variants contribute to the formation of CL/P, however, the contribution of copy number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed, however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our case cohort compared to controls, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR/Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.
2022-12-01 | GSE212165 | GEO
Project description:Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects approximately 1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 x 10(-6). We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P approximately 10(-7): 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 x 10(-7)) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.
| S-EPMC2678639 | biostudies-literature
Project description:BackgroundFew genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.MethodsIn this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.FindingsWe included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).InterpretationWe found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.FundingAsthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.
| S-EPMC6314966 | biostudies-literature
Project description:Background/aimsFasting plasma glucose (FPG) levels correlate with cardiovascular disease and mortality in both diabetic and non-diabetic subjects. G6PC2 encodes a pancreatic islet-specific glucose-6-phosphatase-related protein and G6pc2-null mice were reported to exhibit decreased blood glucose levels. Two recent genome-wide association studies have implicated a role for G6PC2 in regulation of FPGlevels in the general European population and reported the strongest association with the rs560887 SNP. The purpose of this study was to replicate this association in our independent epidemiological samples.MethodsDNA samples from non-Hispanic white Americans (NHWs; n = 623), Hispanic Americans (n = 410) and black Africans (n = 787) were genotyped for rs560887 using TaqMan allelic discrimination.ResultsWhile no minor allele A of rs560887 was observed among blacks, its frequency was 33% in NHWs and 17.5% in Hispanics. The rs560887 minor allele was associated with reduced FPG levels in non-diabetic NHWs (p = 0.002 under an additive model). A similar trend of association was observed in non-diabetic Hispanics (p = 0.076 under a dominant model), which was more pronounced in normoglycemic subjects (p = 0.036).ConclusionsOur results independently confirm the robust association of G6PC2/rs560887 with FPG levels in non-diabetic NHWs. The observed evidence for association in Hispanics warrants further studies in larger samples.
| S-EPMC2855271 | biostudies-literature
Project description:Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time. We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project. A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic β-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level. We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.
| S-EPMC10040618 | biostudies-literature
Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.MethodsWe did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.FindingsWe identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18?×?10-8) located within the Fms-related tyrosine kinase 1 (FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A (VEGFA; OR 0·55, 95% CI 0·41-0·73; p=4·69?×?10-5).InterpretationA common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.FundingInstituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.
| S-EPMC7772505 | biostudies-literature
Project description:Dog ownership has been associated with several complex traits, and there is evidence of genetic influence. We performed a genome-wide association study of dog ownership through a meta-analysis of 31,566 Swedish twins in 5 discovery cohorts and an additional 65,986 European-ancestry individuals in 3 replication cohorts from Sweden, Norway, and the United Kingdom. Association tests with >7.4 million single-nucleotide polymorphisms were meta-analyzed using a fixed effect model after controlling for population structure and relatedness. We identified 2 suggestive loci using discovery cohorts, which did not reach genome-wide significance after meta-analysis with replication cohorts. Single-nucleotide polymorphism-based heritability of dog ownership using linkage disequilibrium score regression was estimated at 0.123 (CI 0.038-0.207) using the discovery cohorts and 0.018 (CI -0.002 to 0.039) when adding in replication cohorts. Negative genetic correlation with complex traits including type 2 diabetes, depression, neuroticism, and asthma was only found using discovery summary data. Furthermore, we did not identify any genes/gene-sets reaching even a suggestive level of significance. This genome-wide association study does not, by itself, provide clear evidence on common genetic variants that influence dog ownership among European-ancestry individuals.
| S-EPMC11304603 | biostudies-literature
Project description:Aims/hypothesisReal-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes.MethodsIn the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA(1c).ResultsWe found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA(1c), fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring.Conclusions/interpretationEven though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be 'prediabetic' or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements.
| S-EPMC2892065 | biostudies-literature