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1.
Biol Psychiatry ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31635762

RESUMO

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

2.
Am J Hypertens ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545351

RESUMO

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study (GWAS) of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic (SBP)≥140 mm Hg and/or diastolic (DBP)≥90 mm Hg) or 4 or more medication classes regardless of BP control (nEA =931, nAA= 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14210, nAA= 2480) and had SBP/DBP <140/90 mm Hg. Treatment-responsive controls (nEA = 5266, nAA= 1817) had BP at goal (<140/90 mm Hg) while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site and principal components for ancestry to examine the association of SNPs with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P=1.1*10-8) and in the race-combined analysis (P=1.5*10-9) using the normotensive control group (rs12046278 OR=0.71[95% CI 0.6-0.8]). SNPs in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

3.
Diabetes ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537524

RESUMO

Early phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early phase insulin response was defined as the difference between the natural logarithm transformed insulin concentrations of the postprandial state at 30 minutes after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (Beta (MAF, P-value): -6.5% (0.32, 3.3x10-8)) located in the ABO gene reached genome-wide significant level (p-value<5 x10-8) and was also replicated successfully (Beta (MAF, P-value): -7.8% (0.32, 7.2x10-5)). The function of the ABO gene was assessed using in vitro shRNA mediated knock-down of gene expression in the murine pancreatic ß-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic ß-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early phase insulin secretion.

4.
Mol Nutr Food Res ; : e1900226, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31432628

RESUMO

SCOPE: Insulin resistance (IR) and inflammation are hallmarks of type 2 diabetes (T2D). The nod-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) initiating IL-1ß inflammation and IR. Interactions between SFA intake and NLRP3-related genetic variants may alter T2D risk factors. METHODS: Meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 19 005) tested interactions between SFA and NLRP3-related single-nucleotide polymorphisms (SNPs) and modulation of fasting insulin, fasting glucose, and homeostasis model assessment of insulin resistance. RESULTS: SFA interacted with rs12143966, wherein each 1% increase in SFA intake increased insulin by 0.0063 IU mL-1 (SE ± 0.002, p = 0.001) per each major (G) allele copy. rs4925663, interacted with SFA (ß ± SE = -0.0058 ± 0.002, p = 0.004) to increase insulin by 0.0058 IU mL-1 , per additional copy of the major (C) allele. Both associations are close to the significance threshold (p < 0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression. CONCLUSION: Two NLRP3-related SNPs showed potential interaction with SFA to modulate fasting insulin. Greater dietary SFA intake accentuates T2D risk, which, subject to functional validation, may be further elaborated depending on NLRP3-related genetic variants.

5.
Am J Kidney Dis ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31358312

RESUMO

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2, is a risk factor for cardiovascular morbidity and mortality. Little is known about low birth weight and risk for CKD in middle-aged adults in the general population. We estimated the causal association between birth weight and eGFR in a Dutch cohort of middle-aged men and women. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 6,671 participants in the Netherlands Epidemiology of Obesity (NEO) Study. Replication study using data for 133,814 participants studied by the CKDGen consortium. EXPOSURE: Birth weight was self-reported and also based on an instrumental variable, 59 birth weight-associated genetic variants, derived from an independent data source. OUTCOME: eGFR at the age of 45 to 65 years. ANALYTICAL APPROACH: We assessed the association between self-reported birth weight and eGFR in the NEO Study using multivariable linear regression, adjusted for age, sex, education, smoking, and alcohol use. The effect of the instrument on eGFR was estimated using separate 2-sample Mendelian randomization analyses: one using individual data from the NEO cohort and one using summary data from the CKDGen consortium. RESULTS: At baseline, mean eGFR was 86±12.4 (SD) mL/min/1.73m2. After multivariable adjustment, self-reported birth weight was not associated with kidney function in middle age. Two-sample Mendelian randomization analysis showed that in the NEO cohort, for each 500-g lower birth weight defined using genetic variants, there was a 3.7 (95% CI, 0.5-6.9)-mL/min/1.73m2 lower eGFR at the age of 45 to 65 years. However, using CKDGen summary-level data, there was a smaller nonsignificant relationship between birth weight and eGFR. LIMITATIONS: Birth weight was self-reported. CONCLUSIONS: Lower birth weight defined using genetic variants was associated with lower eGFRs in Dutch middle-aged adults. However, this finding was not replicated within the CKDGen consortium.

6.
Am J Clin Nutr ; 110(2): 473-484, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31190057

RESUMO

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

7.
J Thromb Haemost ; 17(9): 1535-1543, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31148376

RESUMO

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism. Previous studies have suggested that the CETP TaqI B1/B2 allele is associated with the risk of venous thrombosis (VT). AIM: To investigate the associations between genetically determined CETP concentrations and 22 hemostatic factors in healthy individuals, and the risk of a first VT event, in a large VT case-control study. METHODS: Analyses were performed in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) case-control study. CETP unweighted/weighted genetic risk scores (GRSs) were derived from three single-nucleotide polymorphisms that were identified from a recent genome-wide association study on serum CETP concentrations. The associations between CETP GRSs and 22 hemostatic factors (procoagulant/anticoagulant and fibrinolytic factors) were assessed by linear regression from an additive model in controls (n = 2813). The associations between CETP GRSs and the risk of a first VT were assessed by logistic regression analyses in 3950 VT cases and 4765 controls. RESULTS: In the controls (median age, 49 years; 53% women), both unweighted and weighted GRSs showed that factor VII activity was negatively associated with the genetically determined CETP concentration (weighted GRS ß -3.08 IU/dL per µg/mL genetically determined CETP, 95% confidence interval -5.73 to -0.42). No association was observed with the risk of a first VT. CONCLUSIONS: Genetically determined CETP concentrations only showed a weak negative association with factor VII activity. However, this did not lead to an association with the risk of a first VT.

8.
PLoS One ; 14(6): e0218549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220183

RESUMO

INTRODUCTION: It is crucial to understand the factors that introduce variability before applying metabolomics to clinical and biomarker research. OBJECTIVES: We quantified technical and biological variability of both fasting and postprandial metabolite concentrations measured using 1H NMR spectroscopy in plasma samples. METHODS: In the Netherlands Epidemiology of Obesity study (n = 6,671), 148 metabolite concentrations (101 metabolites belonging to lipoprotein subclasses) were measured under fasting and postprandial states (150 minutes after a mixed liquid meal). Technical variability was evaluated among 265 fasting and 851 postprandial samples, with the identical blood plasma sample being measured twice by the same laboratory protocol. Biological reproducibility was assessed by measuring 165 individuals twice across time for evaluation of short- (<6 months) and long-term (>3 years) biological variability. Intra-class coefficients (ICCs) were used to assess variability. The ICCs of the fasting metabolites were compared with the postprandial metabolites using two-sided paired Wilcoxon test separately for short- and long-term measurements. RESULTS: Both fasting and postprandial metabolite concentrations showed high technical reproducibility using 1H NMR spectroscopy (median ICC = 0.99). Postprandial metabolite concentrations revealed slightly higher ICC scores than fasting ones in short-term repeat measures (median ICC in postprandial and fasting metabolite concentrations 0.72 versus 0.67, Wilcoxon p-value = 8.0×10-14). Variability did not increase further in a long-term repeat measure, with median ICC in postprandial of 0.64 and in fasting metabolite concentrations 0.66. CONCLUSION: Technical reproducibility is excellent. Biological reproducibility of postprandial metabolite concentrations showed a less or equal variability than fasting metabolite concentrations over time.

9.
J Am Heart Assoc ; 8(9): e010810, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31017036

RESUMO

Background Identifying associations between serum metabolites and visceral adipose tissue ( VAT ) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT . Methods and Results Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross-sectional linear regression of individual-level data from participants in MESA (Multi-Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid-lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT ( P=4.88×10-20-1.16×10-3). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched-chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT ( P=1.90×10-35-8.46×10-7), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions We identified and replicated a metabolite panel associated with VAT in 2 community-based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.

11.
Eur J Hum Genet ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420679

RESUMO

According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (µg/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 × 10-22) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 × 10-6). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n ~20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.

12.
Addiction ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209858

RESUMO

AIMS: To use the rs1229984 variant associated with alcohol consumption as an instrument for alcohol consumption to test the causality of the association of alcohol consumption with hay fever, asthma, allergic sensitization and serum total immunoglobulin (Ig)E. DESIGN: Observational and Mendelian randomization analyses using genetic variants as unbiased markers of exposure to estimate causal effects, subject to certain assumptions. SETTING: Europe. PARTICIPANTS: We included a total of 466 434 people aged 15-82 years from 17 population-based studies conducted from 1997 to 2015. MEASUREMENTS: The rs1229984 (ADH1B) was genotyped; alcohol consumption, hay fever and asthma were self-reported. Specific and total IgE were measured from serum samples. FINDINGS: Observational analyses showed that ever-drinking versus non-drinking, but not amount of alcohol intake, was positively associated with hay fever and inversely associated with asthma but not with allergic sensitization or serum total immunoglobulin (Ig)E. However, Mendelian randomization analyses did not suggest that the observational associations are causal. The causal odds ratio (OR) per genetically assessed unit of alcohol/week was an OR = 0.907 [95% confidence interval (CI) = 0.806, 1.019; P = 0.101] for hay fever, an OR = 0.897 (95% CI = 0.790, 1.019; P = 0.095) for asthma, an OR = 0.971 (95% CI =  0.804, 1.174; P = 0.763) for allergic sensitization and a 4.7% change (95% CI = -5.5%, 14.9%; P = 0.366) for total IgE. CONCLUSIONS: In observational analyses, ever-drinking versus not drinking was positively associated with hay fever and negatively associated with asthma. However, the Mendelian randomization results were not consistent with these associations being causal.

13.
J Clin Endocrinol Metab ; 103(12): 4569-4579, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113659

RESUMO

Objective: We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy. Methods: A total of 162 metabolomic measures were analyzed using a nuclear magnetic resonance-based method in people with T2D from four cohort studies (n = 2641) and one replication cohort (n = 395). Linear and logistic regression analyses with adjustment for potential confounders, followed by meta-analyses, were performed to analyze associations with hemoglobin A1c levels, six glucose-lowering drug categories, and insulin initiation during a 7-year follow-up period (n = 698). Results: After Bonferroni correction, 26 measures were associated with insufficient glycemic control (HbA1c >53 mmol/mol). The strongest association was with glutamine (OR, 0.66; 95% CI, 0.61 to 0.73; P = 7.6 × 10-19). In addition, compared with treatment-naive patients, 31 metabolomic measures were associated with glucose-lowering drug use (representing various metabolite categories; P ≤ 3.1 × 10-4 for all). In drug-stratified analyses, associations with insufficient glycemic control were only mildly affected by different glucose-lowering drugs. Five of the 26 metabolomic measures (apolipoprotein A1 and medium high-density lipoprotein subclasses) were also associated with insulin initiation during follow-up in both discovery and replication. The strongest association was observed for medium high-density lipoprotein cholesteryl ester (OR, 0.54; 95% CI, 0.42 to 0.71; P = 4.5 × 10-6). Conclusion: Blood metabolomic measures were associated with present and future glycemic control and might thus provide relevant cues to identify those at increased risk of treatment failure.

14.
Mol Psychiatry ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988085

RESUMO

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

15.
Pharmacogenomics J ; 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29855607

RESUMO

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10-8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

16.
Drug Alcohol Depend ; 188: 94-101, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29758381

RESUMO

BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Éxons/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Uso de Tabaco/genética , Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/diagnóstico , Alcoolismo/epidemiologia , Alcoolismo/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genética , Fatores de Risco , Uso de Tabaco/epidemiologia , Tabagismo/diagnóstico , Tabagismo/genética
17.
Circ Genom Precis Med ; 11(5): e002034, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29728394

RESUMO

BACKGROUND: We aimed to identify independent genetic determinants of circulating CETP (cholesteryl ester transfer protein) to assess causal effects of variation in CETP concentration on circulating lipid concentrations and cardiovascular disease risk. METHODS: A genome-wide association discovery and replication study on serum CETP concentration were embedded in the NEO study (Netherlands Epidemiology of Obesity). Based on the independent identified variants, Mendelian randomization was conducted on serum lipids (NEO study) and coronary artery disease (CAD; CARDIoGRAMplusC4D consortium). RESULTS: In the discovery analysis (n=4248), we identified 3 independent variants (P<5×10-8) that determine CETP concentration. These single-nucleotide polymorphisms were mapped to CETP and replicated in a separate subpopulation (n=1458). Per-allele increase (SE) in serum CETP was 0.32 (0.02) µg/mL for rs247616-C, 0.35 (0.02) µg/mL for rs12720922-A, and 0.12 (0.02) µg/mL for rs1968905-G. Combined, these 3 variants explained 16.4% of the total variation in CETP concentration. One microgram per milliliter increase in genetically determined CETP concentration strongly decreased high-density lipoprotein cholesterol (-0.23 mmol/L; 95% confidence interval, -0.26 to -0.20), moderately increased low-density lipoprotein cholesterol (0.08 mmol/L; 95% confidence interval, 0.00-0.16), and was associated with an odds ratio of 1.08 (95% confidence interval, 0.94-1.23) for CAD risk. CONCLUSIONS: This is the first genome-wide association study identifying independent variants that largely determine CETP concentration. Although high-density lipoprotein cholesterol is not a causal risk factor for CAD, it has been unequivocally demonstrated that low-density lipoprotein cholesterol lowering is proportionally associated with a lower CAD risk. Therefore, the results of our study are fully consistent with the notion that CETP concentration is causally associated with CAD through low-density lipoprotein cholesterol.

18.
Physiol Genomics ; 50(4): 296-297, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29451423

RESUMO

Over 120 Type 2 diabetes (T2D) loci have been identified from genome-wide association studies (GWAS), mainly from Caucasian populations. Very limited knowledge is available on the Saudi Arabian population. In this study, 122 previously reported T2D-related variants from 84 loci were examined in a Saudi Arabian cohort of 1,578 individuals (659 T2D cases and 919 controls). Eleven single nucleotide polymorphisms (SNPs) corresponding to nine independent loci had a P value <0.05. If a more stringent Bonferroni threshold of P = 4.1 × 10-4 ( = 0.05/122) were applied, none of the SNPs would have reached the significance level. Nine of the SNPs with a P value <0.05 showed similar odds ratios as previously described, but rs11605924 ( CRY2) and rs9470794 ( ZFAND3) were in the opposite direction. This study demonstrates the importance of large-scale GWAS in the Saudi Arabian population to identify ethnicity-specific disease-associated variants.

19.
Physiol Genomics ; 50(4): 235-236, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29373077

RESUMO

In 2015, a genome-wide association study described 59 independent signals that showed strong associations with 85 fasting metabolite concentrations as measured by the Biocrates AbsoluteIDQ p150 kit. However, the human body resides in a nonfasting state for the greater part of the day, and the genetic basis of postprandial metabolite concentrations remains largely unknown. We systematically examined these previously identified genetic associations in postprandial metabolite concentrations after a mixed meal. Of these 85 metabolites, 23 were identified with significant changes after the meal, for which 38 gene-metabolite associations were analyzed. Of these 38 associations, 31 gene-metabolite associations were replicated with postprandial metabolite concentrations. These data indicate that the genetics of fasting and postprandial metabolite levels are significantly overlapping.

20.
Am J Hum Genet ; 102(1): 88-102, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29304378

RESUMO

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

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