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1.
Epigenomics ; 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31536415

RESUMO

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31466396

RESUMO

DNA methylation (DNAm) clocks are important biomarkers of cellular aging and are associated with a variety of age-related chronic diseases and all-cause mortality. Examining the relationship between education and lifestyle risk factors for age-related diseases and multiple DNAm clocks can increase the understanding of how risk factors contribute to aging at the cellular level. This study explored the association between education or lifestyle risk factors for age-related diseases and the acceleration of four DNAm clocks, including intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), and GrimAge acceleration (GrimAA) in the African American participants of the Genetic Epidemiology Network of Arteriopathy. We performed both cross-sectional and longitudinal analyses. In cross-sectional analyses, gender, education, BMI, smoking, and alcohol consumption were all independently associated with GrimAA, whereas only some of them were associated with other clocks. The effect of smoking and education on GrimAA varied by gender. Longitudinal analyses suggest that age and BMI continued to increase GrimAA, and that age and current smoking continued to increase PhenoAA after controlling DNAm clocks at baseline. In conclusion, education and common lifestyle risk factors were associated with multiple DNAm clocks. However, the association with each risk factor varied by clock, which suggests that different clocks may capture adverse effects from different environmental stimuli.

3.
Mol Genet Genomic Med ; 7(10): e00788, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407531

RESUMO

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography. METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates. RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10-8 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population. CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.

4.
Nat Hum Behav ; 3(9): 950-961, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358974

RESUMO

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

5.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
7.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

8.
PLoS One ; 14(4): e0214061, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973896

RESUMO

BACKGROUND: Gene expression may be an important biological mediator in associations between social factors and health. However, previous studies were limited by small sample sizes and use of differing cell types with heterogeneous expression patterns. We use a large population-based cohort with gene expression measured solely in monocytes to investigate associations between seven social factors and expression of genes previously found to be sensitive to social factors. METHODS: We employ three methodological approaches: 1) omnibus test for the entire gene set (Global ANCOVA), 2) assessment of each association individually (linear regression), and 3) machine learning method that performs variable selection with correlated predictors (elastic net). RESULTS: In global analyses, significant associations with the a priori defined socially sensitive gene set were detected for major or lifetime discrimination and chronic burden (p = 0.019 and p = 0.047, respectively). Marginally significant associations were detected for loneliness and adult socioeconomic status (p = 0.066, p = 0.093, respectively). No associations were significant in linear regression analyses after accounting for multiple testing. However, a small percentage of gene expressions (up to 11%) were associated with at least one social factor using elastic net. CONCLUSION: The Global ANCOVA and elastic net findings suggest that a small percentage of genes may be "socially sensitive," (i.e. demonstrate differential expression by social factor), yet single gene approaches such as linear regression may be ill powered to capture this relationship. Future research should further investigate the biological mechanisms through which social factors act to influence gene expression and how systemic changes in gene expression affect overall health.

9.
Diabetes ; 68(5): 1073-1083, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30936141

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

10.
Hum Genet ; 138(4): 375-388, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30852652

RESUMO

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.


Assuntos
Caderinas/genética , Loci Gênicos , Redes e Vias Metabólicas/genética , Metabolismo/genética , Transcriptoma , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
11.
Epigenetics ; 14(4): 383-391, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30915882

RESUMO

INTRODUCTION: Cigarette smoking has been associated with adverse health outcomes for mothers and children and is a major contributor to heart disease. Although cigarette smoking is known to affect the epigenome, few studies have been done in African American populations. In this study, we investigated the association between cigarette smoking and DNA methylation (DNAm) among African Americans from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study (InterGEN), and the Genetic Epidemiology Network of Arteriopathy (GENOA). METHODS: The InterGEN study aims to examine the effects of genetic and psychological factors on blood pressure among African American women and their children. Current cigarette smoking was assessed at baseline. DNAm of saliva was assessed using the 850K EPIC Illumina BeadChip for Epigenome-Wide Association analyses. A replication study was conducted among 1100 participants in the GENOA study using the same BeadChip. RESULTS: After controlling for age, body mass index, population structure and cell composition, 26 epigenome-wide significant sites (FDR q < 0.05) were identified, including the AHRR and PHF14 genes associated with atherosclerosis and lung disease, respectively. Six novel CpG sites were discovered in the InterGEN sample and replicated in the GENOA sample. Genes mapped include RARA, FSIP1, ALPP, PIK3R5, KIAA0087, and MGAT3, which were largely associated with cancer development. CONCLUSION: We observed significant epigenetic associations between smoking and disease-associated genes (e.g., cardiovascular disease, lung cancer). Six novel CpG sites were identified and replicated across saliva and blood samples.

12.
Diabetes ; 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30796027

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes. We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at over 400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding p=6.9×10-6) with replication at Bonferroni corrected p<8.6×10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (p=2.5×10-4). Hypomethylation of the same CpG was also associated with risk for new-onset type 2 diabetes (p=0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for type 2 diabetes. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

13.
Biol Res Nurs ; 21(3): 279-285, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30781968

RESUMO

With the rapid advancement of omics-based research, particularly big data such as genome- and epigenome-wide association studies that include extensive environmental and clinical variables, data analytics have become increasingly complex. Researchers face significant challenges regarding how to analyze multifactorial data and make use of the findings for clinical translation. The purpose of this article is to provide a scientific exemplar for use of genetic burden scores as a data analysis method for studies with both genotype and DNA methylation data in which the goal is to evaluate associations with chronic conditions such as metabolic syndrome (MetS). This study included 739 African American men and women from the Genetic Epidemiology Network of Arteriopathy Study who met diagnostic criteria for MetS and had available genetic and epigenetic data. Genetic burden scores for evaluated genes were not significant after multiple testing corrections, but DNA methylation at 2 CpG sites (dihydroorotate dehydrogenase cg22381196 pFDR = .014; CTNNA3 cg00132141 pFDR = .043) was significantly associated with MetS after controlling for multiple comparisons. Interactions between the marginally significant CpG sites and burden scores, however, were not significant. More work is required in this area to identify intermediate biological pathways influenced by environmental, genetic, and epigenetic variation that may explain the high prevalence of MetS among African Americans. This study does serve, however, as an example of the use of the genetic burden score as an alternative data analysis approach for complex studies involving the analysis of genetic and epigenetic data simultaneously.


Assuntos
Afro-Americanos/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética , Síndrome Metabólica/genética , Síndrome Metabólica/fisiopatologia , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
14.
Epigenetics ; 14(2): 171-184, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30764717

RESUMO

Changes in DNA methylation may be a potential mechanism that mediates the effects of smoking on physiological function and subsequent disease risk. Given the dynamic nature of the epigenome, longitudinal studies are indispensable for investigating smoking-induced methylation changes over time. Using blood samples collected approximately five years apart in 380 African Americans (mean age 60.7 years) from the Genetic Epidemiology Network of Arteriopathy (GENOA) study, we measured DNA methylation levels using Illumina HumanMethylation BeadChips. We evaluated the association between Phase 1 smoking status and rate of methylation change, using generalized estimating equation models. Among the 6958 CpG sites examined, smoking status was associated with methylation change for 22 CpGs (false discovery rate q < 0.1), with the majority (91%) becoming less methylated over time. Methylation change was greater in ever smokers than never smokers, and the absolute differences in rates of change ranged from 0.18 to 0.77 per decade in M value, equivalent to a ß value change of 0.013 to 0.047 per decade. Significant enrichment was observed for CpG islands, enhancers, and DNAse hypersensitivity sites (p < 0.05). Although biological pathway analyses were not significant, most of the 22 CpGs were within genes known to be associated with cardiovascular disease, cancers, and aging. In conclusion, we identified epigenetic signatures for cigarette smoking that may have been missed in cross-sectional analyses, providing insight into the epigenetic effect of smoking and highlighting the importance of longitudinal analysis in understanding the dynamic human epigenome.

15.
Am J Hum Genet ; 104(2): 260-274, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639324

RESUMO

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

16.
Nat Genet ; 51(2): 237-244, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643251

RESUMO

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Fumar/genética , Tabagismo/genética , Feminino , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Risco , Tabaco/efeitos adversos
17.
Biol Psychiatry ; 85(11): 946-955, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30679032

RESUMO

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

18.
Hum Genet ; 138(2): 199-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30671673

RESUMO

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 16/genética , Exoma , Ligação Genética , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Processamento Alternativo/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Processamento de RNA/genética , Recombinases/genética
19.
Soc Sci Med ; 2018 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-30449520

RESUMO

Both social and genetic factors contribute to cognitive impairment and decline, yet genetic factors identified through genome-wide association studies (GWAS) explain only a small portion of trait variability. This "missing heritability" may be due to rare, potentially functional, genetic variants not assessed by GWAS, as well as gene-by-social factor interactions not explicitly modeled. Gene-by-social factor interactions may also operate differently across race/ethnic groups. We selected 39 genes that had significant, replicated associations with cognition, dementia, and related traits in published GWAS. Using gene-based analysis (SKAT/iSKAT), we tested whether common and/or rare variants were associated with episodic memory performance and decline either alone or through interaction with education in >10,000 European ancestry (EA) and >2200 African ancestry (AA) respondents from the Health and Retirement Study (HRS). Nine genes in EA and five genes in AA were associated with memory performance or decline (p < 0.05), and these effects did not attenuate after adjusting for education. Interaction between education and CLPTM1 on memory performance was significant in AA (p = 0.003; FDR-adjusted p = 0.038) and nominally significant in EA (p = 0.026). In both ethnicities, low memory performance was associated with CLPTM1 genotype (rs10416261) only for those with less than high school education, and effects persisted after adjusting for APOE ε4. For over 70% of gene-by-education interactions across the genome that were at least nominally significant in either ethnic group (p < 0.05), genetic effects were only observed for those with less than high school education. These results suggest that genetic effects on memory identified in this study are not mediated by education, but there may be important gene-by-education interactions across the genome, including in the broader APOE genomic region, which operate independently of APOE ε4. This work illustrates the importance of developing theoretical frameworks and methodological approaches for integrating social and genomic data to study cognition across ethnic groups.

20.
PLoS One ; 13(9): e0204622, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30261045

RESUMO

Reovirus infection induces dramatic changes in host mRNA expression. We utilized oligonucleotide microarrays to measure cellular mRNA decay rates in mock- or reovirus-infected murine L929 cells to determine if changes in host mRNA expression are a consequence of reovirus-induced alterations in cellular mRNA stability. Our analysis detected a subset of cellular transcripts that were coordinately induced and stabilized following infection with the reovirus isolates c87 and c8, strains that led to an inhibition of cellular translation, but not following infection with Dearing, a reovirus isolate that did not negatively impact cellular translation. The induced and stabilized transcripts encode multiple regulators of TGF- ß signaling, including components of the Smad signaling network and apoptosis/survival pathways. The coordinate induction, through mRNA stabilization, of multiple genes that encode components of TGF-ß signaling pathways represents a novel mechanism by which the host cell responds to reovirus infection.

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