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1.
Twin Res Hum Genet ; : 1-7, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31526404

RESUMO

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King's College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several 'omic' technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the 'TwinsUK' resource with the scientific community - interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK.

2.
Nat Commun ; 10(1): 2164, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092820

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.


Assuntos
Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Interferon Tipo I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lúpus Eritematoso Sistêmico/genética , Regiões 3' não Traduzidas/genética , Adulto , Fatores Etários , Estudos de Casos e Controles , Feminino , Genes Ligados ao Cromossomo X/imunologia , Predisposição Genética para Doença , Humanos , Interferon Tipo I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Regiões Promotoras Genéticas/genética , Fatores Sexuais , Receptor 7 Toll-Like/genética
3.
Am J Hum Genet ; 104(6): 1013-1024, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31130283

RESUMO

Adipose tissue is an important endocrine organ with a role in many cardiometabolic diseases. It is comprised of a heterogeneous collection of cell types that can differentially impact disease phenotypes. Cellular heterogeneity can also confound -omic analyses but is rarely taken into account in analysis of solid-tissue transcriptomes. Here, we investigate cell-type heterogeneity in two population-level subcutaneous adipose-tissue RNA-seq datasets (TwinsUK, n = 766 and the Genotype-Tissue Expression project [GTEx], n = 326) by estimating the relative proportions of four distinct cell types (adipocytes, macrophages, CD4+ T cells, and micro-vascular endothelial cells). We find significant cellular heterogeneity within and between the TwinsUK and GTEx adipose datasets. We find that adipose cell-type composition is heritable and confirm the positive association between adipose-resident macrophage proportion and obesity (high BMI), but we find a stronger BMI-independent association with dual-energy X-ray absorptiometry (DXA) derived body-fat distribution traits. We benchmark the impact of adipose-tissue cell composition on a range of standard analyses, including phenotype-gene expression association, co-expression networks, and cis-eQTL discovery. Our results indicate that it is critical to account for cell-type composition when combining adipose transcriptome datasets in co-expression analysis and in differential expression analysis with obesity-related traits. We applied gene expression by cell-type proportion interaction models (G × Cell) to identify 26 cell-type-specific expression quantitative trait loci (eQTLs) in 20 genes, including four autoimmune disease genome-wide association study (GWAS) loci. These results identify cell-specific eQTLs and demonstrate the potential of in silico deconvolution of bulk tissue to identify cell-type-restricted regulatory variants.

4.
Clin Epigenetics ; 11(1): 27, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760334

RESUMO

BACKGROUND: Genetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease. METHODS: Self-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples. RESULTS: Epigenome-wide analyses in blood identified one CpG-site (cg21245277 in ZNF804A) associated with gingival bleeding (FDR = 0.03, nominal p value = 7.17e-8) and 58 sites associated with tooth mobility (FDR < 0.05) with the top signals in IQCE and XKR6. Epigenetic variation at 28 candidate regions (247 CpG-sites) for chronic periodontitis showed an enrichment for association with periodontal traits, and signals in eight genes (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, and CXCL1) were significant in both traits. The methylation-phenotype association signals validated in buccal samples, and a subset (25%) also validated in adipose tissue. CONCLUSIONS: Epigenome-wide analyses in adult female twins identified specific DNA methylation changes linked to self-reported periodontal disease. Future work will explore the environmental basis and functional impact of these results to infer potential for strategic personalized treatments and prevention of chronic periodontitis.


Assuntos
Metilação de DNA , Doenças em Gêmeos/genética , Estudo de Associação Genômica Ampla/métodos , Periodontite/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Estudos Transversais , Epigênese Genética , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de RNA/métodos , Reino Unido
5.
Elife ; 82019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30775970

RESUMO

Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (TBRG4, MTPAP and LONP1), implicating genetic mechanisms that act in trans across the two genomes. We replicate ~21% of associations with independent tissue-matched datasets and find genetic variants linked to these nuclear loci that are associated with cardio-metabolic phenotypes and Vitiligo, supporting a potential role for variable mitochondrial-encoded gene expression in complex disease.

6.
Clin Epigenetics ; 10(1): 126, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30342560

RESUMO

BACKGROUND: Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear. METHODS: We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat. RESULTS: We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation. CONCLUSIONS: Our results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.

7.
BMC Genomics ; 19(1): 659, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30193568

RESUMO

BACKGROUND: Intermittent fasting and time-restricted diets are associated with lower risk biomarkers for cardio-metabolic disease. The shared mechanisms underpinning the similar physiological response to these events is not established, but circadian rhythm could be involved. Here we investigated the transcriptional response to fasting in a large cross-sectional study of adipose and skin tissue from healthy volunteers (N = 625) controlling for confounders of circadian rhythm: time of day and season. RESULTS: We identified 367 genes in adipose and 79 in skin whose expression levels were associated (FDR < 5%) with hours of fasting conditionally independent of time of day and season, with 19 genes common to both tissues. Among these genes, we replicated 38 in human, 157 in non-human studies, and 178 are novel associations. Fasting-responsive genes were enriched for regulation of and response to circadian rhythm. We identified 99 genes in adipose and 54 genes in skin whose expression was associated to time of day; these genes were also enriched for circadian rhythm processes. In genes associated to both exposures the effect of time of day was stronger and in an opposite direction to that of hours fasted. We also investigated the relationship between fasting and genetic regulation of gene expression, including GxE eQTL analysis to identify personal responses to fasting. CONCLUSION: This study robustly implicates circadian rhythm genes in the response to hours fasting independently of time of day, seasonality, age and BMI. We identified tissue-shared and tissue-specific differences in the transcriptional response to fasting in a large sample of healthy volunteers.


Assuntos
Tecido Adiposo/metabolismo , Ritmo Circadiano/genética , Jejum/fisiologia , Pele/metabolismo , Transcriptoma/fisiologia , Feminino , Interação Gene-Ambiente , Humanos , Pessoa de Meia-Idade , Especificidade de Órgãos , Locos de Características Quantitativas/genética , Fatores de Risco
8.
Nat Commun ; 9(1): 3472, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135520

RESUMO

In the original version of this Article, Supplementary Table 10 contained incorrect primer sequences for the mobility shift assay for SNP rs4776984. These errors have now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.

10.
Nat Genet ; 50(6): 790-795, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29808030

RESUMO

The human gut microbiome plays a key role in human health 1 , but 16S characterization lacks quantitative functional annotation 2 . The fecal metabolome provides a functional readout of microbial activity and can be used as an intermediate phenotype mediating host-microbiome interactions 3 . In this comprehensive description of the fecal metabolome, examining 1,116 metabolites from 786 individuals from a population-based twin study (TwinsUK), the fecal metabolome was found to be only modestly influenced by host genetics (heritability (H2) = 17.9%). One replicated locus at the NAT2 gene was associated with fecal metabolic traits. The fecal metabolome largely reflects gut microbial composition, explaining on average 67.7% (±18.8%) of its variance. It is strongly associated with visceral-fat mass, thereby illustrating potential mechanisms underlying the well-established microbial influence on abdominal obesity. Fecal metabolic profiling thus is a novel tool to explore links among microbiome composition, host phenotypes, and heritable complex traits.

11.
Nat Commun ; 9(1): 1512, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29666371

RESUMO

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development. Here we perform promoter Capture Hi-C in human adipocytes to investigate interactions between gene promoters and distal elements as a transcription-regulating mechanism contributing to these phenotypes. We find that promoter-interacting elements in human adipocytes are enriched for adipose-related transcription factor motifs, such as PPARG and CEBPB, and contribute to heritability of cis-regulated gene expression. We further intersect these data with published genome-wide association studies for BMI and BMI-related metabolic traits to identify the genes that are under genetic cis regulation in human adipocytes via chromosomal interactions. This integrative genomics approach identifies four cis-eQTL-eGene relationships associated with BMI or obesity-related traits, including rs4776984 and MAP2K5, which we further confirm by EMSA, and highlights 38 additional candidate genes.

12.
Nat Genet ; 50(4): 572-580, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29632379

RESUMO

Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.

13.
Hum Mol Genet ; 27(4): 732-741, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29228364

RESUMO

Changes in the mean and variance of gene expression with age have consequences for healthy aging and disease development. Age-dependent changes in phenotypic variance have been associated with a decline in regulatory functions leading to increase in disease risk. Here, we investigate age-related mean and variance changes in gene expression measured by RNA-seq of fat, skin, whole blood and derived lymphoblastoid cell lines (LCLs) expression from 855 adult female twins. We see evidence of up to 60% of age effects on transcription levels shared across tissues, and 47% of those on splicing. Using gene expression variance and discordance between genetically identical MZ twin pairs, we identify 137 genes with age-related changes in variance and 42 genes with age-related discordance between co-twins; implying the latter are driven by environmental effects. We identify four eQTLs whose effect on expression is age-dependent (FDR 5%). Combined, these results show a complicated mix of environmental and genetically driven changes in expression with age. Using the twin structure in our data, we show that additive genetic effects explain considerably more of the variance in gene expression than aging, but less that other environmental factors, potentially explaining why reliable expression-derived biomarkers for healthy-aging have proved elusive compared with those derived from methylation.

14.
Nat Genet ; 49(12): 1747-1751, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29058714

RESUMO

Genetic association mapping produces statistical links between phenotypes and genomic regions, but identifying causal variants remains difficult. Whole-genome sequencing (WGS) can help by providing complete knowledge of all genetic variants, but it is financially prohibitive for well-powered GWAS studies. We performed mapping of expression quantitative trait loci (eQTLs) with WGS and RNA-seq, and found that lead eQTL variants called with WGS were more likely to be causal. Through simulations, we derived properties of causal variants and used them to develop a method for identifying likely causal SNPs. We estimated that 25-70% of causal variants were located in open-chromatin regions, depending on the tissue and experiment. Finally, we identified a set of high-confidence causal variants and showed that these were more enriched in GWAS associations than other eQTLs. Of those, we found 65 associations with GWAS traits and provide examples in which genes implicated by expression are functionally validated as being relevant for complex traits.


Assuntos
Perfilação da Expressão Gênica/métodos , Variação Genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes
15.
Nat Genet ; 49(4): 568-578, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28263315

RESUMO

Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10-11). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Metaboloma/genética , Adulto , Idoso , Sangue , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Locos de Características Quantitativas
16.
Am J Hum Genet ; 100(3): 428-443, 2017 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-28257690

RESUMO

Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 × 10-8) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.


Assuntos
Doenças Cardiovasculares/genética , Regulação da Expressão Gênica , Síndrome Metabólica/genética , Locos de Características Quantitativas , Gordura Subcutânea/metabolismo , Idoso , Animais , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Reprodutibilidade dos Testes , Transativadores/genética , Transativadores/metabolismo
17.
Hum Mol Genet ; 26(5): 1003-1017, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28062664

RESUMO

Studies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression. RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence. We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through the integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes. We discovered the greatest frequency of candidate-causal eQTLs using exon-level RNA-Seq, and identified novel SLE susceptibility genes (e.g. NADSYN1 and TCF7) that were concealed using microarrays, including four non-coding RNAs. Many of these eQTLs were found to influence the expression of several genes, supporting the notion that risk haplotypes may harbour multiple functional effects. Novel SLE associated splicing events were identified in the T-reg restricted transcription factor, IKZF2, and other candidate genes (e.g. WDFY4) through asQTL mapping using the Geuvadis cohort. We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications. We conclude that to better understand the true functional consequence of regulatory variants, quantification by RNA-Seq should be performed at the exon-level as a minimum, and run in parallel with gene and splice-junction level quantification.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Locos de Características Quantitativas/genética , RNA não Traduzido/genética , Processamento Alternativo/genética , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/biossíntese , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Mapeamento Cromossômico , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Polimorfismo de Nucleotídeo Único , Fator 1 de Transcrição de Linfócitos T/biossíntese , Fator 1 de Transcrição de Linfócitos T/genética
18.
Genome Biol ; 17(1): 248, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27908293

RESUMO

BACKGROUND: Despite their nearly identical genomes, males and females differ in risk, incidence, prevalence, severity and age-at-onset of many diseases. Sexual dimorphism is also seen in human autosomal gene expression, and has largely been explored by examining the contribution of genotype-by-sex interactions to variation in gene expression. RESULTS: In this study, we use data from a mixture of pedigree and unrelated individuals with verified European ancestry to investigate the sex-specific genetic architecture of gene expression measured in whole blood across n=1048 males and n=1005 females by treating gene expression intensities in the sexes as two distinct traits and estimating the genetic correlation (r G) between them. These correlations measure the similarity of the combined additive genetic effects of all single-nucleotide polymorphisms across the autosomal chromosomes, and thus the level of common genetic control of gene expression across the sexes. Genetic correlations are estimated across the sexes for the expression levels of 12,528 autosomal gene expression probes using bivariate GREML, and tested for differences in autosomal genetic control of gene expression across the sexes. Overall, no deviation of the distribution of test statistics is observed from that expected under the null hypothesis of a common autosomal genetic architecture for gene expression across the sexes. CONCLUSIONS: These results suggest that males and females share the same common genetic control of gene expression.


Assuntos
Regulação da Expressão Gênica/genética , Genótipo , Caracteres Sexuais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único
19.
Am J Hum Genet ; 99(3): 567-579, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27588447

RESUMO

Obesity is a global epidemic that is causally associated with a range of diseases, including type 2 diabetes and cardiovascular disease, at the population-level. However, there is marked heterogeneity in obesity-related outcomes among individuals. This might reflect genotype-dependent responses to adiposity. Given that adiposity, measured by BMI, is associated with widespread changes in gene expression and regulatory variants mediate the majority of known complex trait loci, we sought to identify gene-by-BMI (G × BMI) interactions on the regulation of gene expression in a multi-tissue RNA-sequencing (RNA-seq) dataset from the TwinsUK cohort (n = 856). At a false discovery rate of 5%, we identified 16 cis G × BMI interactions (top cis interaction: CHURC1, rs7143432, p = 2.0 × 10(-12)) and one variant regulating 53 genes in trans (top trans interaction: ZNF423, rs3851570, p = 8.2 × 10(-13)), all in adipose tissue. The interactions were adipose-specific and enriched for variants overlapping adipocyte enhancers, and regulated genes were enriched for metabolic and inflammatory processes. We replicated a subset of the interactions in an independent adipose RNA-seq dataset (deCODE genetics, n = 754). We also confirmed the interactions with an alternate measure of obesity, dual-energy X-ray absorptiometry (DXA)-derived visceral-fat-volume measurements, in a subset of TwinsUK individuals (n = 682). The identified G × BMI regulatory effects demonstrate the dynamic nature of gene regulation and reveal a functional mechanism underlying the heterogeneous response to obesity. Additionally, we have provided a web browser allowing interactive exploration of the dataset, including of association between expression, BMI, and G × BMI regulatory effects in four tissues.


Assuntos
Adiposidade/genética , Transcriptoma/genética , Absorciometria de Fóton , Índice de Massa Corporal , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Conjuntos de Dados como Assunto , Feminino , Humanos , Gordura Intra-Abdominal/anatomia & histologia , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de RNA , Gêmeos/genética , Reino Unido
20.
Obesity (Silver Spring) ; 24(6): 1380-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27129722

RESUMO

OBJECTIVE: Abdominal obesity is associated with increased risk of type 2 diabetes (T2D) and cardiovascular disease. The aim of this study was to assess whether metabolomic markers of T2D and blood pressure (BP) act on these traits via visceral fat (VF) mass. METHODS: Metabolomic profiling of 280 fasting plasma metabolites was conducted on 2,401 women from TwinsUK. The overlap was assessed between published metabolites associated with T2D, insulin resistance, or BP and those that were identified to be associated with VF (after adjustment for covariates) measured by dual-energy X-ray absorptiometry. RESULTS: In addition to glucose, six metabolites were strongly associated with both VF mass and T2D: lactate and branched-chain amino acids, all of them related to metabolism and the tricarboxylic acid cycle; on average, 38.5% of their association with insulin resistance was mediated by their association with VF mass. Five metabolites were associated with BP and VF mass including the inflammation-associated peptide HWESASXX, the steroid hormone androstenedione, lactate, and palmitate. On average, 29% of their effect on BP was mediated by their association with VF mass. CONCLUSIONS: Little overlap was found between the metabolites associated with BP and those associated with insulin resistance via VF mass.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Gordura Intra-Abdominal/metabolismo , Síndrome Metabólica/fisiopatologia , Absorciometria de Fóton , Idoso , Aminoácidos de Cadeia Ramificada/sangue , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Ciclo do Ácido Cítrico , Estudos Transversais , Feminino , Humanos , Ácido Láctico/sangue , Modelos Lineares , Metabolômica , Pessoa de Meia-Idade
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