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1.
Elife ; 82019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31746734

RESUMO

The MHC region is highly associated with autoimmune and infectious diseases. Here we conduct an in-depth interrogation of associations between genetic variation, gene expression and disease. We create a comprehensive map of regulatory variation in the MHC region using WGS from 419 individuals to call eight-digit HLA types and RNA-seq data from matched iPSCs. Building on this regulatory map, we explored GWAS signals for 4,083 traits, detecting colocalization for 180 disease loci with eQTLs. We show that eQTL analyses taking HLA type haplotypes into account have substantially greater power compared with only using single variants. We examined the association between the 8.1 ancestral haplotype and delayed colonization in Cystic Fibrosis, postulating that downregulation of RNF5 expression is the likely causal mechanism. Our study provides insights into the genetic architecture of the MHC region and pinpoints disease associations that are due to differential expression of HLA genes and non-HLA genes.

2.
Stem Cell Reports ; 13(5): 924-938, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31668852

RESUMO

Despite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Comparing the transcriptomes of CM-fated and EPDC-fated iPSCs, we discovered that 91 signature genes and X chromosome dosage differences are associated with these two distinct cardiac developmental trajectories. In an independent set of 39 iPSCs differentiated into CMs, we confirmed that sex and transcriptional differences affect cardiac-fate outcome. Our study provides novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence their response to differentiation stimuli and, hence, cardiac cell fate.

3.
iScience ; 21: 681-694, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733514

RESUMO

Pancreatic endocrine cell differentiation is orchestrated by the action of transcription factors that operate in a gene regulatory network to activate endocrine lineage genes and repress lineage-inappropriate genes. MicroRNAs (miRNAs) are important modulators of gene expression, yet their role in endocrine cell differentiation has not been systematically explored. Here we characterize miRNA-regulatory networks active in human endocrine cell differentiation by combining small RNA sequencing, miRNA over-expression, and network modeling approaches. Our analysis identified Let-7g, Let-7a, miR-200a, miR-127, and miR-375 as endocrine-enriched miRNAs that drive endocrine cell differentiation-associated gene expression changes. These miRNAs are predicted to target different transcription factors, which converge on genes involved in cell cycle regulation. When expressed in human embryonic stem cell-derived pancreatic progenitors, these miRNAs induce cell cycle exit and promote endocrine cell differentiation. Our study delineates the role of miRNAs in human endocrine cell differentiation and identifies miRNAs that could facilitate endocrine cell reprogramming.

4.
Haematologica ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582554

RESUMO

Venous thromboembolism is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of venous thromboembolism, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of venous thromboembolism. Cases with incident venous thromboembolism (n= 640) and a randomly selected age-weighted sub-cohort (n=3734) were derived from a population-based cohort (the Tromso study). Cox-regression was used to estimate hazard ratios with 95% confidence intervals for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7 95% CI 1.2-2.3) increased risk of venous thromboembolism compared to non-carriers. Cancer patients homozygous for the FGG variant had a 2-fold (HR 2.0 95% CI 1.1-3.6) higher risk of venous thromboembolism than cancer patients without the variant. Moreover, the 6-month cumulative incidence of venous thromboembolism among cancer patients was 6.4% (95% CI, 3.5%-11.6%) in homozygous carriers of FGG and 3.1% (95% CI, 2.3%-4.7%) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (Synergy index: 1.81, 95% CI: 1.02-3.21, Attributable proportion: 0.43, 95% CI: 0.11-0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded synergistic effect on the risk of venous thromboembolism.

5.
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.

6.
Blood ; 134(19): 1645-1657, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

7.
Nat Commun ; 10(1): 3644, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409799

RESUMO

B cell development is a highly regulated process involving multiple differentiation steps, yet many details regarding this pathway remain unknown. Sequencing of patients with B cell-restricted immunodeficiency reveals autosomal dominant mutations in TOP2B. TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development. We use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization.

8.
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
9.
Stem Cell Reports ; 12(6): 1342-1353, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31080113

RESUMO

We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to those of native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observed high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal RPE. We performed fine mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele-specific expression of a non-coding transcript. Our study thus provides a potential mechanism underlying the association of the VEGFA locus with AMD.

10.
Blood ; 133(25): 2651-2663, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30923040

RESUMO

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+ Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

11.
Nat Commun ; 10(1): 1054, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837461

RESUMO

While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression.


Assuntos
Cromatina/genética , DNA/genética , Regulação da Expressão Gênica , Histonas/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Idoso , Linhagem Celular , Cromatina/metabolismo , DNA/metabolismo , Feminino , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos , Conformação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma , Adulto Jovem
12.
J Thromb Haemost ; 17(5): 749-758, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30773804

RESUMO

Essentials Prothrombotic genotypes may agument the risk of venous thromboembolism (VTE) after ischemic stroke. We studied this effect in a case-cohort study using a genetic risk score. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of VTE. The risk of VTE in stroke patients increased with an increasing number of risk alleles. SUMMARY: Background Patients with ischemic stroke have a transiently increased risk of subsequent venous thromboembolism (VTE). Prothrombotic genotypes may augment VTE risk under conditions of high thrombosis risk related to stroke. Aims To investigate the effect of prothrombotic genotypes in patients with ischemic stroke on the risk of VTE in a population-based case-cohort study. Methods Cases with incident VTE (n = 664) and a randomly selected age-weighted subcohort (n = 1817) were sampled from three surveys of the Tromsø Study (1994-2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914) single-nucleotide polymorphisms (SNPs). Cox regression models were used to calculate hazard ratios (HRs) for incident VTE according to individual SNPs and categories of risk alleles (5-SNP score; 0-1, 2, 3-4 and ≥ 5) in participants with and without ischemic stroke. Results There were 192 patients with incident stroke, of whom 43 developed VTE during a median of 15.2 years of follow-up. The risk alleles of individual SNPs augmented the elevated VTE risk brought about by ischemic stroke. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of overall VTE (HR 1.5, 95% confidence interval [CI] 1.3-1.8) and an 80% higher relative risk of provoked VTE (HR 1.8, 95% CI 1.5-2.1). Stroke patients with ≥ 5 risk alleles had a 12-fold (HR 11.7, 95% CI 4.1-33.3) higher relative risk of VTE than stroke-free participants with 0-1 risk alleles. Conclusions Prothrombotic genotypes increased the risk of VTE in stroke patients, and the risk increased with an increasing number of risk alleles.

13.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
14.
Circ Genom Precis Med ; 11(12): e002170, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30562114

RESUMO

BACKGROUND: Identifying genetic variation associated with plasma protein levels, and the mechanisms by which they act, could provide insight into alterable processes involved in regulation of protein levels. Although protein levels can be affected by genetic variants, their estimation can also be biased by missense variants in coding exons causing technical artifacts. Integrating genome sequence genotype data with mass spectrometry-based protein level estimation could reduce bias, thereby improving detection of variation that affects RNA or protein metabolism. METHODS: Here, we integrate the blood plasma protein levels of 664 proteins from 165 participants of the Tromsø Study, measured via tandem mass tag mass spectrometry, with whole-exome sequencing data to identify common and rare genetic variation associated with peptide and protein levels (protein quantitative trait loci [pQTLs]). We additionally use literature and database searches to prioritize putative functional variants for each pQTL. RESULTS: We identify 109 independent associations (36 protein and 73 peptide) and use genotype data to exclude 49 (4 protein and 45 peptide) as technical artifacts. We describe 2 particular cases of rare variation: 1 associated with the complement pathway and 1 with platelet degranulation. We identify putative functional variants and show that pQTLs act through diverse molecular mechanisms that affect both RNA and protein metabolism. CONCLUSIONS: We show that although the majority of pQTLs exert their effects by modulating RNA metabolism, many affect protein levels directly. Our work demonstrates the extent by which pQTL studies are affected by technical artifacts and highlights how prioritizing the functional variant in pQTL studies can lead to insights into the molecular steps by which a protein may be regulated.


Assuntos
Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Variação Genética , Estudos de Coortes , Éxons , Feminino , Genótipo , Humanos , Masculino , Espectrometria de Massas , Proteoma/genética , Locos de Características Quantitativas , Sequenciamento Completo do Exoma
15.
Stem Cell Reports ; 11(3): 828-841, 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30122443

RESUMO

To facilitate understanding of human cardiomyocyte (CM) subtype specification, and the study of ventricular CM biology in particular, we developed a broadly applicable strategy for enrichment of ventricular cardiomyocytes (VCMs) derived from human embryonic stem cells (hESCs). A bacterial artificial chromosome transgenic H9 hESC line in which GFP expression was driven by the human ventricular-specific myosin light chain 2 (MYL2) promoter was generated, and screened to identify cell-surface markers specific for MYL2-GFP-expressing VCMs. A CD77+/CD200- cell-surface signature facilitated isolation of >97% cardiac troponin I-positive cells from H9 hESC differentiation cultures, with 65% expressing MYL2-GFP. This study provides a tool for VCM enrichment when using some, but not all, human pluripotent stem cell lines. Tools generated in this study can be utilized toward understanding CM subtype specification, and enriching for VCMs for therapeutic applications.

16.
Hum Genet ; 137(6-7): 447-458, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29978320

RESUMO

Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures. The introduction of the IFT88 p.Arg266* variant in the homozygous state in HeLa cells by CRISPR-Cas9 genome-editing revealed that the mutant transcript undergoes nonsense-mediated decay leading to a significant depletion of IFT88 transcript. Additionally, abnormal ciliogenesis was observed in these cells. These observations suggest that the rare and unique combination of IFT88 alleles observed in this study provide insight into the physiological role of IFT88 in humans and the likely mechanism underlying retinal pathology in the pedigree with IRD.

17.
Cell Rep ; 24(4): 883-894, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30044985

RESUMO

To understand the mutational burden of human induced pluripotent stem cells (iPSCs), we sequenced genomes of 18 fibroblast-derived iPSC lines and identified different classes of somatic mutations based on structure, origin, and frequency. Copy-number alterations affected 295 kb in each sample and strongly impacted gene expression. UV-damage mutations were present in ∼45% of the iPSCs and accounted for most of the observed heterogeneity in mutation rates across lines. Subclonal mutations (not present in all iPSCs within a line) composed 10% of point mutations and, compared with clonal variants, showed an enrichment in active promoters and increased association with altered gene expression. Our study shows that, by combining WGS, transcriptome, and epigenome data, we can understand the mutational burden of each iPSC line on an individual basis and suggests that this information could be used to prioritize iPSC lines for models of specific human diseases and/or transplantation therapy.

20.
Genetics ; 207(4): 1301-1312, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29074555

RESUMO

Expression quantitative trait loci (eQTL) studies have typically used single-variant association analysis to identify genetic variants correlated with gene expression. However, this approach has several drawbacks: causal variants cannot be distinguished from nonfunctional variants in strong linkage disequilibrium, combined effects from multiple causal variants cannot be captured, and low-frequency (<5% MAF) eQTL variants are difficult to identify. While these issues possibly could be overcome by using sparse polygenic models, which associate multiple genetic variants with gene expression simultaneously, the predictive performance of these models for eQTL studies has not been evaluated. Here, we assessed the ability of three sparse polygenic models (Lasso, Elastic Net, and BSLMM) to identify causal variants, and compared their efficacy to single-variant association analysis and a fine-mapping model. Using simulated data, we determined that, while these methods performed similarly when there was one causal SNP present at a gene, BSLMM substantially outperformed single-variant association analysis for prioritizing causal eQTL variants when multiple causal eQTL variants were present (1.6- to 5.2-fold higher recall at 20% precision), and identified up to 2.3-fold more low frequency variants as the top eQTL SNP. Analysis of real RNA-seq and whole-genome sequencing data of 131 iPSC samples showed that the eQTL SNPs identified by BSLMM had a higher functional enrichment in DHS sites and were more often low-frequency than those identified with single-variant association analysis. Our study showed that BSLMM is a more effective approach than single-variant association analysis for prioritizing multiple causal eQTL variants at a single gene.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Herança Multifatorial/genética , Locos de Características Quantitativas/genética , Expressão Gênica/genética , Variação Genética , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único/genética
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