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1.
Nat Genet ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

2.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

3.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

4.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
5.
Am J Transplant ; 19(8): 2262-2273, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30920136

RESUMO

Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.

6.
Am J Nephrol ; 49(3): 193-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808845

RESUMO

BACKGROUND: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. METHODS: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. RESULTS: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. CONCLUSIONS: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

7.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
8.
Am J Hum Genet ; 103(5): 691-706, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

9.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

10.
Psychosom Med ; 80(3): 252-262, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29381659

RESUMO

OBJECTIVE: A strong genetic predisposition for type 2 diabetes mellitus (T2DM) may aggravate the negative effects of low socioeconomic position (SEP) in the etiology of the disorder. This study aimed to examine cross-sectional and longitudinal associations and interactions of a genetic risk score (GRS) and SEP with T2DM and to investigate whether clinical and behavioral risk factors can explain these associations and interactions. METHODS: We used data from 13,027 genotyped participants from the Lifelines study. The GRS was based on single-nucleotide polymorphisms genome-wide associated with T2DM and was categorized into tertiles. SEP was measured as educational level. T2DM was based on biological markers, recorded medication use, and self-reports. Cross-sectional and longitudinal associations and interactions between the GRS and SEP on T2DM were examined. RESULTS: The combination of a high GRS and low SEP had the strongest association with T2DM in cross-sectional (odds ratio = 3.84, 95% confidence interval = 2.28-6.46) and longitudinal analyses (hazard ratio = 2.71, 1.39-5.27), compared with a low GRS and high SEP. Interaction between a high GRS and a low SEP was observed in cross-sectional (relative excess risk due to interaction = 1.85, 0.65-3.05) but not in longitudinal analyses. Clinical and behavioral risk factors mostly explained the observed associations and interactions. CONCLUSIONS: A high GRS combined with a low SEP provides the highest risk for T2DM. These factors also exacerbated each other's impact cross-sectionally but not longitudinally. Preventive measures should target individual and contextual factors of this high-risk group to reduce the risk of T2DM.

11.
Nephrol Dial Transplant ; 33(10): 1757-1764, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29294079

RESUMO

Background: Meta-analysis of cross-sectional genome-wide association studies (GWAS) on creatinine-estimated glomerular filtration rate (eGFRcrea) identified 53 single-nucleotide polymorphisms (SNPs). These SNP effects can be aggregated into a genetic risk score (GRS) for chronic kidney disease (CKD). To assess its clinical utility, we examined associations with creatinine-estimated kidney outcomes, both cross-sectionally and longitudinally. Additionally, we examined associations with cystatin C-estimated kidney outcomes to verify that a GRS based on eGFRcrea SNPs represents the genetics underlying kidney function. Methods: In the community-based Prevention of REnal and Vascular ENdstage Disease (PREVEND) study, we assessed eGFRcrea and eGFRcysc at baseline and four follow-up examinations. The GRS comprised 53 SNPs for eGFRcrea weighted for reported effect-sizes. We adjusted for baseline demographics and renal risk factors. Results: We included 3649 subjects (median age 49 years, 52% male, median follow-up 11 years, n = 85 baseline CKD, n = 154 incident CKD). At baseline, a higher GRS associated with lower eGFRcrea {adjusted B [95% confidence interval (CI)] = -2.05 (-2.45 to - 1.65) mL/min/1.73 m2, P < 0.001} and higher CKD prevalence [adjusted odds ratio (95% CI) = 1.41 (1.12-1.77), P = 0.002]. During follow-up, a higher GRS associated with higher CKD incidence [adjusted hazard ratio (95% CI) = 1.28 (1.09-1.50), P = 0.004], but no longer significantly after adjustment for baseline eGFR. No significant association with eGFRcrea decline was found. Associations with cystatin C-estimated outcomes were similar. Conclusions: The GRS robustly associated with baseline CKD and eGFR, independent of known risk factors. Associations with incident CKD were likely due to low baseline eGFR, not accelerated eGFR decline. The GRS for eGFRcrea likely represents the genetics underlying kidney function, not creatinine metabolism or underlying aetiologies. To improve the clinical utility of GWAS results for CKD, these need to specifically address eGFR decline and CKD incidence.

12.
Nat Hum Behav ; 1(10): 757-765, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29051922

RESUMO

Meta-analyses of genome-wide association studies (GWAS), which dominate genetic discovery are based on data from diverse historical time periods and populations. Genetic scores derived from GWAS explain only a fraction of the heritability estimates obtained from whole-genome studies on single populations, known as the 'hidden heritability' puzzle. Using seven sampling populations (N=35,062), we test whether hidden heritability is attributed to heterogeneity across sampling populations and time, showing that estimates are substantially smaller from across compared to within populations. We show that the hidden heritability varies substantially: from zero (height), to 20% for BMI, 37% for education, 40% for age at first birth and up to 75% for number of children. Simulations demonstrate that our results more likely reflect heterogeneity in phenotypic measurement or gene-environment interaction than genetic heterogeneity. These findings have substantial implications for genetic discovery, suggesting that large homogenous datasets are required for behavioural phenotypes and that gene-environment interaction may be a central challenge for genetic discovery.

13.
Nat Commun ; 8(1): 744, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963451

RESUMO

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.


Assuntos
Estatura/genética , Peso Corporal/genética , Grupo com Ancestrais do Continente Europeu/genética , Antropometria , Índice de Massa Corporal , Tamanho Corporal/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Relação Cintura-Quadril
14.
PLoS Med ; 14(9): e1002383, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28898252

RESUMO

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Variação Genética , Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/genética , Diabetes Mellitus Tipo 2/epidemiologia , Hemoglobina A Glicada/metabolismo , Humanos , Fenótipo , Risco
15.
Psychoneuroendocrinology ; 85: 88-95, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28843169

RESUMO

Cortisol is an important stress hormone affected by a variety of biological and environmental factors, such as the circadian rhythm, exercise and psychological stress. Cortisol is mostly measured using blood or saliva samples. A number of genetic variants have been found to contribute to cortisol levels with these methods. While the effects of several specific single genetic variants is known, the joint genome-wide contribution to cortisol levels is unclear. Our aim was to estimate the amount of cortisol variance explained by common single nucleotide polymorphisms, i.e. the SNP heritability, using a variety of cortisol measures, cohorts and analysis approaches. We analyzed morning plasma (n=5705) and saliva levels (n=1717), as well as diurnal saliva levels (n=1541), in the Rotterdam Study using genomic restricted maximum likelihood estimation. Additionally, linkage disequilibrium score regression was fitted on the results of genome-wide association studies (GWAS) performed by the CORNET consortium on morning plasma cortisol (n=12,597) and saliva cortisol (n=7703). No significant SNP heritability was detected for any cortisol measure, sample or analysis approach. Point estimates ranged from 0% to 9%. Morning plasma cortisol in the CORNET cohorts, the sample with the most power, had a 6% [95%CI: 0-13%] SNP heritability. The results consistently suggest a low SNP heritability of these acute and short-term measures of cortisol. The low SNP heritability may reflect the substantial environmental and, in particular, situational component of these cortisol measures. Future GWAS will require very large sample sizes. Alternatively, more long-term cortisol measures such as hair cortisol samples are needed to discover further genetic pathways regulating cortisol concentrations.


Assuntos
Estudo de Associação Genômica Ampla , Hidrocortisona/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Países Baixos , Saliva/química
17.
Hypertension ; 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28739976

RESUMO

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

18.
Nat Commun ; 8: 15805, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28613276

RESUMO

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74

19.
J Am Soc Nephrol ; 28(8): 2311-2321, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28360221

RESUMO

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.


Assuntos
Loci Gênicos , Plasma/química , Simportadores de Sódio-Bicarbonato/genética , Sódio/análise , Fatores de Transcrição/genética , Desequilíbrio Hidroeletrolítico/sangue , Desequilíbrio Hidroeletrolítico/genética , Idoso , Grupos de Populações Continentais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar
20.
Eur J Hum Genet ; 25(7): 877-885, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28401901

RESUMO

Despite the recent explosive rise in number of genetic markers for complex disease traits identified in genome-wide association studies, there is still a large gap between the known heritability of these traits and the part explained by these markers. To gauge whether this 'heritability gap' is closing, we first identified genome-wide significant SNPs from the literature and performed replication analyses for 32 highly relevant traits from five broad disease areas in 13 436 subjects of the Lifelines Cohort. Next, we calculated the variance explained by multi-SNP genetic risk scores (GRSs) for each trait, and compared it to their broad- and narrow-sense heritabilities captured by all common SNPs. The majority of all previously-associated SNPs (median=75%) were significantly associated with their respective traits. All GRSs were significant, with unweighted GRSs generally explaining less phenotypic variance than weighted GRSs, for which the explained variance was highest for height (15.5%) and varied between 0.02 and 6.7% for the other traits. Broad-sense common-SNP heritability estimates were significant for all traits, with the additive effect of common SNPs explaining 48.9% of the variance for height and between 5.6 and 39.2% for the other traits. Dominance effects were uniformly small (0-1.5%) and not significant. On average, the variance explained by the weighted GRSs accounted for only 10.7% of the common-SNP heritability of the 32 traits. These results indicate that GRSs may not yet be ready for accurate personalized prediction of complex disease traits limiting widespread adoption in clinical practice.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Fenótipo , Característica Quantitativa Herdável , Contagem de Células Sanguíneas , Pressão Sanguínea/genética , Genes Dominantes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/normas , Frequência Cardíaca/genética , Humanos , Polimorfismo de Nucleotídeo Único , Respiração/genética
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