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1.
Genome Biol ; 20(1): 255, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779666

RESUMO

BACKGROUND: The 3-dimensional (3D) conformation of chromatin inside the nucleus is integral to a variety of nuclear processes including transcriptional regulation, DNA replication, and DNA damage repair. Aberrations in 3D chromatin conformation have been implicated in developmental abnormalities and cancer. Despite the importance of 3D chromatin conformation to cellular function and human health, little is known about how 3D chromatin conformation varies in the human population, or whether DNA sequence variation between individuals influences 3D chromatin conformation. RESULTS: To address these questions, we perform Hi-C on lymphoblastoid cell lines from 20 individuals. We identify thousands of regions across the genome where 3D chromatin conformation varies between individuals and find that this variation is often accompanied by variation in gene expression, histone modifications, and transcription factor binding. Moreover, we find that DNA sequence variation influences several features of 3D chromatin conformation including loop strength, contact insulation, contact directionality, and density of local cis contacts. We map hundreds of quantitative trait loci associated with 3D chromatin features and find evidence that some of these same variants are associated at modest levels with other molecular phenotypes as well as complex disease risk. CONCLUSION: Our results demonstrate that common DNA sequence variants can influence 3D chromatin conformation, pointing to a more pervasive role for 3D chromatin conformation in human phenotypic variation than previously recognized.

2.
Nat Genet ; 51(10): 1506-1517, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570892

RESUMO

The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes.

3.
Nat Commun ; 10(1): 2078, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064983

RESUMO

Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk.


Assuntos
Cromatina/metabolismo , Diabetes Mellitus Tipo 2/genética , Redes Reguladoras de Genes/genética , Ilhotas Pancreáticas/metabolismo , Proteínas de Ligação a RNA/genética , Adulto , Animais , Núcleo Celular/metabolismo , Montagem e Desmontagem da Cromatina/genética , Diabetes Mellitus Tipo 2/patologia , Elementos Facilitadores Genéticos/genética , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Glucose/metabolismo , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Conformação Molecular , Locos de Características Quantitativas/genética , Proteínas de Ligação a RNA/metabolismo
4.
Genome Med ; 11(1): 19, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914061

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified several hundred susceptibility loci for type 2 diabetes (T2D). One critical, but unresolved, issue concerns the extent to which the mechanisms through which these diverse signals influencing T2D predisposition converge on a limited set of biological processes. However, the causal variants identified by GWAS mostly fall into a non-coding sequence, complicating the task of defining the effector transcripts through which they operate. METHODS: Here, we describe implementation of an analytical pipeline to address this question. First, we integrate multiple sources of genetic, genomic and biological data to assign positional candidacy scores to the genes that map to T2D GWAS signals. Second, we introduce genes with high scores as seeds within a network optimization algorithm (the asymmetric prize-collecting Steiner tree approach) which uses external, experimentally confirmed protein-protein interaction (PPI) data to generate high-confidence sub-networks. Third, we use GWAS data to test the T2D association enrichment of the "non-seed" proteins introduced into the network, as a measure of the overall functional connectivity of the network. RESULTS: We find (a) non-seed proteins in the T2D protein-interaction network so generated (comprising 705 nodes) are enriched for association to T2D (p = 0.0014) but not control traits, (b) stronger T2D-enrichment for islets than other tissues when we use RNA expression data to generate tissue-specific PPI networks and (c) enhanced enrichment (p = 3.9 × 10- 5) when we combine the analysis of the islet-specific PPI network with a focus on the subset of T2D GWAS loci which act through defective insulin secretion. CONCLUSIONS: These analyses reveal a pattern of non-random functional connectivity between candidate causal genes at T2D GWAS loci and highlight the products of genes including YWHAG, SMAD4 or CDK2 as potential contributors to T2D-relevant islet dysfunction. The approach we describe can be applied to other complex genetic and genomic datasets, facilitating integration of diverse data types into disease-associated networks.

5.
EMBO J ; 38(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918008

RESUMO

Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in cis (locally) or in trans (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of cis-acting lncRNAs and protein-coding genes involved in innate immunity. A total of 229 gene pairs were identified, many of which were commonly regulated by signaling through multiple TLRs and were involved in the cytokine responses to infection by group B Streptococcus We focused on elucidating the function of one lncRNA, named lnc-MARCKS or ROCKI (Regulator of Cytokines and Inflammation), which was induced by multiple TLR stimuli and acted as a master regulator of inflammatory responses. ROCKI interacted with APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) to form a ribonucleoprotein complex at the MARCKS promoter. In turn, ROCKI-APEX1 recruited the histone deacetylase HDAC1, which removed the H3K27ac modification from the promoter, thus reducing MARCKS transcription and subsequent Ca2+ signaling and inflammatory gene expression. Finally, genetic variants affecting ROCKI expression were linked to a reduced risk of certain inflammatory and infectious disease in humans, including inflammatory bowel disease and tuberculosis. Collectively, these data highlight the importance of cis-acting lncRNAs in TLR signaling, innate immunity, and pathophysiological inflammation.

6.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

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


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
7.
Hum Mol Genet ; 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30407494

RESUMO

The extent to which shared genetic risk contributes to T1D and T2D etiology is unknown. In this study, we generated T1D association data of 15k samples imputed into the HRC panel which we compared to published T2D association data imputed into 1000 Genomes. The effects of genetic variants on T1D and T2D risk at known loci and genome-wide were positively correlated. Increased risk of T1D and T2D was correlated with higher fasting insulin and glucose level and decreased birth weight, among other correlations. Variants with T1D and T2D association were further enriched in pancreatic, adipose, B cell, and endoderm regulatory elements. We fine-mapped causal variants at known loci and found evidence for co-localization at five signals, four of which had same direction of effect. Shared risk variants were associated with quantitative measures of islet function and early growth, and were expression QTLs in relevant tissues. We further identified a shared variant at GLIS3 in islet accessible chromatin with allelic effects on enhancer activity. Our findings identify a shared genetic risk involving effects on islet function as well as insulin resistance, growth and development in the etiology of T1D and T2D, supporting a role for T2D-relevant processes in addition to autoimmunity in T1D risk.

9.
Elife ; 72018 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-29412141

RESUMO

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

11.
Proc Natl Acad Sci U S A ; 115(2): 379-384, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29279374

RESUMO

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética , Americanos Mexicanos/genética , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/patologia , Saúde da Família , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Locos de Características Quantitativas/genética , Sequenciamento Completo do Genoma/métodos
12.
Sci Data ; 4: 170179, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29257133

RESUMO

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Variação Genética , Grupo com Ancestrais do Continente Europeu , Humanos
13.
Curr Diab Rep ; 17(9): 72, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28741265

RESUMO

PURPOSE OF REVIEW: Deciphering the mechanisms of type 2 diabetes (T2DM) risk loci can greatly inform on disease pathology. This review discusses current knowledge of mechanisms through which genetic variants influence T2DM risk and considerations for future studies. RECENT FINDINGS: Over 100 T2DM risk loci to date have been identified. Candidate causal variants at risk loci map predominantly to non-coding sequence. Physiological, epigenomic and gene expression data suggest that variants at many known T2DM risk loci affect pancreatic islet regulation, although variants at other loci also affect protein function and regulatory processes in adipose, pre-adipose, liver, skeletal muscle and brain. The effects of T2DM variants on regulatory activity in these tissues appear largely, but not exclusively, due to altered transcription factor binding. Putative target genes of T2DM variants have been defined at an increasing number of loci and some, such as FTO, may entail several genes and multiple tissues. Gene networks in islets and adipocytes have been implicated in T2DM risk, although the molecular pathways of risk genes remain largely undefined. Efforts to fully define the mechanisms of T2DM risk loci are just beginning. Continued identification of risk mechanisms will benefit from combining genetic fine-mapping with detailed phenotypic association data, high-throughput epigenomics data from diabetes-relevant tissue, functional screening of candidate genes and genome editing of cellular and animal models.


Assuntos
Diabetes Mellitus Tipo 2/genética , Loci Gênicos , Predisposição Genética para Doença , Animais , Modelos Animais de Doenças , Variação Genética , Humanos , Fatores de Risco
14.
Diabetes ; 66(11): 2888-2902, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28566273

RESUMO

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Variação Genética , Humanos
15.
PLoS Genet ; 13(5): e1006728, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28498854

RESUMO

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Hipertensão/genética , Herança Multifatorial , Afro-Americanos/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Caderinas/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Masculino , Proteínas de Membrana/genética , Camundongos , Polimorfismo de Nucleotídeo Único
16.
Diabetes ; 66(7): 2019-2032, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28341696

RESUMO

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/genética , Jejum/metabolismo , Resistência à Insulina/genética , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Afro-Americanos/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Finlândia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Hispano-Americanos/genética , Humanos , Razão de Chances
18.
Am J Hum Genet ; 100(2): 238-256, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132686

RESUMO

Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in ß cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, ß-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult ß cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in ß cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the ß cell.


Assuntos
Diabetes Mellitus Tipo 2/genética , Insulina/metabolismo , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alelos , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Clonagem Molecular , Diabetes Mellitus Tipo 2/sangue , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Regulação da Expressão Gênica , Variação Genética , Homeostase , Humanos , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Fígado/metabolismo , Camundongos , Proinsulina/sangue , Proinsulina/metabolismo , Locos de Características Quantitativas , Transcriptoma
19.
Nat Commun ; 8: 16015, 2017 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29313844

RESUMO

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.


Assuntos
Genética Populacional , Estudo de Associação Genômica Ampla , Força da Mão , Mãos/fisiologia , Actinas/genética , Adulto , Idoso , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Fator de Crescimento Transformador alfa/genética , Reino Unido
20.
Nat Genet ; 49(1): 17-26, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27841877

RESUMO

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.


Assuntos
Tecido Adiposo/patologia , Doenças Cardiovasculares/fisiopatologia , Genômica/métodos , Resistência à Insulina/genética , Doenças Metabólicas/fisiopatologia , Obesidade/complicações , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Índice de Massa Corporal , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Obesidade/genética , Fenótipo
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