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1.
Nat Commun ; 10(1): 357, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664637

RESUMO

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.


Assuntos
Alelos , Loci Gênicos , Variação Genética , RNA Mensageiro/genética , Crânio/metabolismo , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefalometria , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência do Gene , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Crânio/anatomia & histologia
2.
Nat Genet ; 51(2): 343-353, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30692680

RESUMO

Loci discovered by genome-wide association studies predominantly map outside protein-coding genes. The interpretation of the functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking by which to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Here we propose a novel approach that leverages genome-wide association studies' findings with regulatory or functional annotations to classify features relevant to a phenotype of interest. Within our framework, we account for major sources of confounding not offered by current methods. We further assess enrichment of genome-wide association studies for 19 traits within Encyclopedia of DNA Elements- and Roadmap-derived regulatory regions. We characterize unique enrichment patterns for traits and annotations driving novel biological insights. The method is implemented in standalone software and an R package, to facilitate its application by the research community.


Assuntos
Doença/genética , Genoma/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Anotação de Sequência Molecular/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Software
4.
Nat Commun ; 9(1): 3738, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30218040

RESUMO

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

5.
Am J Hum Genet ; 100(6): 865-884, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552196

RESUMO

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.


Assuntos
Antropometria , Genoma Humano , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Análise de Sequência de DNA/métodos , Estatura/genética , Estudos de Coortes , Metilação de DNA/genética , Bases de Dados Genéticas , Feminino , Variação Genética , Humanos , Lipodistrofia/genética , Masculino , Metanálise como Assunto , Obesidade/genética , Mapeamento Físico do Cromossomo , Caracteres Sexuais , Síndrome , Reino Unido
6.
Nat Genet ; 48(11): 1303-1312, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27668658

RESUMO

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.


Assuntos
Loci Gênicos , Genoma Humano , Estudo de Associação Genômica Ampla , Cardiopatias/genética , Doenças Hematológicas/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Locos de Características Quantitativas , Análise de Sequência de DNA
7.
Genome Biol ; 17: 61, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-27036880

RESUMO

BACKGROUND: The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age. RESULTS: We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution. CONCLUSIONS: DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease.


Assuntos
Metilação de DNA , DNA/sangue , Variação Genética , Locos de Características Quantitativas , Adolescente , Criança , Pré-Escolar , Ilhas de CpG , Bases de Dados Genéticas , Epigênese Genética , Feminino , Estudos de Associação Genética , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Gravidez
8.
Cephalalgia ; 36(7): 640-7, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26646788

RESUMO

BACKGROUND: Migraine is a common episodic brain disorder characterized by recurrent attacks of severe unilateral headache and additional neurological symptoms. Two main migraine types can be distinguished based on the presence of aura symptoms that can accompany the headache: migraine with aura and migraine without aura. Multiple genetic and environmental factors confer disease susceptibility. Recent genome-wide association studies (GWAS) indicate that migraine susceptibility genes are involved in various pathways, including neurotransmission, which have already been implicated in genetic studies of monogenic familial hemiplegic migraine, a subtype of migraine with aura. METHODS: To further explore the genetic background of migraine, we performed a gene set analysis of migraine GWAS data of 4954 clinic-based patients with migraine, as well as 13,390 controls. Curated sets of synaptic genes and sets of genes predominantly expressed in three glial cell types (astrocytes, microglia and oligodendrocytes) were investigated. DISCUSSION: Our results show that gene sets containing astrocyte- and oligodendrocyte-related genes are associated with migraine, which is especially true for gene sets involved in protein modification and signal transduction. Observed differences between migraine with aura and migraine without aura indicate that both migraine types, at least in part, seem to have a different genetic background.


Assuntos
Astrócitos , Transtornos de Enxaqueca/genética , Oligodendroglia , Adulto , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos
9.
Nature ; 526(7571): 82-90, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26367797

RESUMO

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.


Assuntos
Doença/genética , Variação Genética/genética , Genoma Humano/genética , Saúde , Adiponectina/sangue , Alelos , Estudos de Coortes , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Genética Médica , Genética Populacional , Estudo de Associação Genômica Ampla , Genômica , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Anotação de Sequência Molecular , Receptores de LDL/genética , Padrões de Referência , Análise de Sequência de DNA , Triglicerídeos/sangue , Reino Unido
10.
Nat Commun ; 6: 8111, 2015 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-26368830

RESUMO

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Variação Genética , Genótipo , Haplótipos , Modelos Estatísticos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Genoma Humano , Humanos , Itália , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Reino Unido , Adulto Jovem
11.
Bioinformatics ; 31(24): 4029-31, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26315906

RESUMO

UNLABELLED: High-throughput sequencing technologies survey genetic variation at genome scale and are increasingly used to study the contribution of rare and low-frequency genetic variants to human traits. As part of the Cohorts arm of the UK10K project, genetic variants called from low-read depth (average 7×) whole genome sequencing of 3621 cohort individuals were analysed for statistical associations with 64 different phenotypic traits of biomedical importance. Here, we describe a novel genome browser based on the Biodalliance platform developed to provide interactive access to the association results of the project. AVAILABILITY AND IMPLEMENTATION: The browser is available at http://www.uk10k.org/dalliance.html. Source code for the Biodalliance platform is available under a BSD license from http://github.com/dasmoth/dalliance, and for the LD-display plugin and backend from http://github.com/dasmoth/ldserv.


Assuntos
Estudos de Associação Genética , Variação Genética , Genoma Humano , Software , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Desequilíbrio de Ligação
13.
Nat Commun ; 5: 4871, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25225788

RESUMO

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.


Assuntos
Alelos , Apolipoproteína C-III/genética , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Processamento Alternativo , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Gêmeos/genética
14.
Diabetes ; 63(11): 3785-97, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24947352

RESUMO

Upper- and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m(2)). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depot-specific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper- and lower-body obesity.


Assuntos
Tecido Adiposo/metabolismo , Doenças Cardiovasculares/metabolismo , Obesidade/metabolismo , Gordura Abdominal/metabolismo , Adulto , Metilação de DNA , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Gordura Subcutânea Abdominal/metabolismo , Proteínas com Domínio T/metabolismo
15.
PLoS Genet ; 9(6): e1003500, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23754948

RESUMO

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.


Assuntos
Antropometria/métodos , Pesos e Medidas Corporais , Estudo de Associação Genômica Ampla , Caracteres Sexuais , Estatura/genética , Índice de Massa Corporal , Peso Corporal/genética , Feminino , Loci Gênicos , Genoma Humano , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Circunferência da Cintura/genética , Relação Cintura-Quadril
16.
Nat Genet ; 45(5): 501-12, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23563607

RESUMO

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.


Assuntos
Antropometria , Estatura/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Índice de Massa Corporal , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , Metanálise como Assunto , Fenótipo , Relação Cintura-Quadril
17.
Nat Genet ; 44(10): 1084-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22941192

RESUMO

Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.


Assuntos
Mapeamento Cromossômico , Regulação da Expressão Gênica , Transcrição Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Interação Gene-Ambiente , Ligação Genética , Humanos , Linfócitos/metabolismo , Pessoa de Meia-Idade , Modelos Genéticos , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Pele/metabolismo , Gordura Subcutânea/metabolismo
18.
PLoS Genet ; 8(2): e1002505, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22383892

RESUMO

Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and whole blood (WB), from 29 MetS cases and 44 controls. Co-expression network analysis for each tissue independently identified nine, six, and zero MetS-associated modules of coexpressed genes in ABD, GLU, and WB, respectively. Of 8,992 probesets expressed in ABD or GLU, 685 (7.6%) were expressed in ABD and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU) = 0.89), seven of which were associated with MetS (FDR P<0.01). The strongest associated module, significantly enriched for immune response-related processes, contained 94/620 (15%) genes with inter-depot differences. In an independent cohort of 145/141 twins with ABD and WB longitudinal expression data, median variability in ABD due to familiality was greater for MetS-associated versus un-associated modules (ABD: 0.48 versus 0.18, P = 0.08; GLU: 0.54 versus 0.20, P = 7.8×10(-4)). Cis-eQTL analysis of probesets associated with MetS (FDR P<0.01) and/or inter-depot differences (FDR P<0.01) provided evidence for 32 eQTLs. Corresponding eSNPs were tested for association with MetS-related phenotypes in two GWAS of >100,000 individuals; rs10282458, affecting expression of RARRES2 (encoding chemerin), was associated with body mass index (BMI) (P = 6.0×10(-4)); and rs2395185, affecting inter-depot differences of HLA-DRB1 expression, was associated with high-density lipoprotein (P = 8.7×10(-4)) and BMI-adjusted waist-to-hip ratio (P = 2.4×10(-4)). Since many genes and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations.


Assuntos
Tecido Adiposo/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Síndrome Metabólica/genética , Índice de Massa Corporal , Quimiocinas/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Cadeias HLA-DRB1/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Síndrome Metabólica/patologia , Especificidade de Órgãos , Fenótipo , Locos de Características Quantitativas
19.
PLoS One ; 6(11): e27338, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22102887

RESUMO

To understand how miRNAs contribute to the molecular phenotype of adipose tissues and related traits, we performed global miRNA expression profiling in subcutaneous abdominal and gluteal adipose tissue of 70 human subjects and characterised which miRNAs were differentially expressed between these tissues. We found that 12% of the miRNAs were significantly differentially expressed between abdominal and gluteal adipose tissue (FDR adjusted p<0.05) in the primary study, of which 59 replicated in a follow-up study of 40 additional subjects. Further, 14 miRNAs were found to be associated with metabolic syndrome case-control status in abdominal tissue and three of these replicated (primary study: FDR adjusted p<0.05, replication: p<0.05 and directionally consistent effect). Genome-wide genotyping was performed in the 70 subjects to enable miRNA expression quantitative trait loci (eQTL) analysis. Candidate miRNA eQTLs were followed-up in the additional 40 subjects and six significant, independent cis-located miRNA eQTLs (primary study: p<0.001; replication: p<0.05 and directionally consistent effect) were identified. Finally, global mRNA expression profiling was performed in both tissues to enable association analysis between miRNA and target mRNA expression levels. We find 22% miRNAs in abdominal and 9% miRNAs in gluteal adipose tissue with expression levels significantly associated with the expression of corresponding target mRNAs (FDR adjusted p<0.05). Taken together, our results indicate a clear difference in the miRNA molecular phenotypic profile of abdominal and gluteal adipose tissue, that the expressions of some miRNAs are influenced by cis-located genetic variants and that miRNAs are associated with expression levels of their predicted mRNA targets.


Assuntos
Gordura Abdominal/fisiologia , Biomarcadores/metabolismo , Nádegas/fisiologia , MicroRNAs/genética , Locos de Características Quantitativas , RNA Mensageiro/genética , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Síndrome Metabólica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética
20.
PLoS Genet ; 7(9): e1002270, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21931564

RESUMO

We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)

Assuntos
Estudo de Associação Genômica Ampla , Redes e Vias Metabólicas/genética , Metaboloma/genética , Locos de Características Quantitativas/genética , Seleção Genética , Acetiltransferases/genética , Acetiltransferases/metabolismo , Dimetilaminas/sangue , Dimetilaminas/metabolismo , Feminino , Haplótipos , Humanos , Isobutiratos/metabolismo , Isobutiratos/urina , Espectroscopia de Ressonância Magnética , Metilaminas/metabolismo , Metilaminas/urina , Polimorfismo de Nucleotídeo Único
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