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3.
Nucleic Acids Res ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570217

RESUMO

Interpreting the molecular mechanism of genomic variations and their causal relationship with diseases/traits are important and challenging problems in the human genetic study. To provide comprehensive and context-specific variant annotations for biologists and clinicians, here, by systematically integrating over 4TB genomic/epigenomic profiles and frequently-used annotation databases from various biological domains, we develop a variant annotation database, called VannoPortal. In general, the database has following major features: (i) systematically integrates 40 genome-wide variant annotations and prediction scores regarding allele frequency, linkage disequilibrium, evolutionary signature, disease/trait association, tissue/cell type-specific epigenome, base-wise functional prediction, allelic imbalance and pathogenicity; (ii) equips with our recent novel index system and parallel random-sweep searching algorithms for efficient management of backend databases and information extraction; (iii) greatly expands context-dependent variant annotation to incorporate large-scale epigenomic maps and regulatory profiles (such as EpiMap) across over 33 tissue/cell types; (iv) compiles many genome-scale base-wise prediction scores for regulatory/pathogenic variant classification beyond protein-coding region; (v) enables fast retrieval and direct comparison of functional evidence among linked variants using highly interactive web panel in addition to plain table; (vi) introduces many visualization functions for more efficient identification and interpretation of functional variants in single web page. VannoPortal is freely available at http://mulinlab.org/vportal.

4.
Stroke ; 52(12): 3926-3937, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34565175

RESUMO

BACKGROUND AND PURPOSE: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. METHODS: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study-identified genetic variants of Vit-D mechanistic pathways (rs2060793, rs4588, and rs7041; F statistic, 73; P<0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. RESULTS: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P=0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48-0.81]; P<0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35-0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42-0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30-0.81]). CONCLUSIONS: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

5.
EBioMedicine ; 71: 103530, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34455394

RESUMO

BACKGROUND: Biliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution, especially for nonsyndromic BA (common form: > 85%) remains poorly defined. METHODS: We conducted whole exome sequencing on 89 nonsyndromic BA trios to identify rare variants contributing to BA etiology. Functional evaluation using patients' liver biopsies, human cell and zebrafish models were performed. Clinical impact on respiratory system was assessed with clinical evaluation, nasal nitric oxide (nNO), high speed video analysis and transmission electron microscopy. FINDINGS: We detected rare, deleterious de novo or biallelic variants in liver-expressed ciliary genes in 31.5% (28/89) of the BA patients. Burden test revealed 2.6-fold (odds ratio (OR) [95% confidence intervals (CI)]= 2.58 [1.15-6.07], adjusted p = 0.034) over-representation of rare, deleterious mutations in liver-expressed ciliary gene set in patients compared to controls. Functional analyses further demonstrated absence of cilia in the BA livers with KIF3B and TTC17 mutations, and knockdown of PCNT, KIF3B and TTC17 in human control fibroblasts and cholangiocytes resulted in reduced number of cilia. Additionally, CRISPR/Cas9-engineered zebrafish knockouts of KIF3B, PCNT and TTC17 displayed reduced biliary flow. Abnormally low level of nNO was detected in 80% (8/10) of BA patients carrying deleterious ciliary mutations, implicating the intrinsic ciliary defects. INTERPRETATION: Our findings support strong genetic susceptibility for nonsyndromic BA. Ciliary gene mutations leading to cholangiocyte cilia malformation and dysfunction could be a key biological mechanism in BA pathogenesis. FUNDING: The study is supported by General Research Fund, HMRF Commissioned Paediatric Research at HKCH and Li Ka Shing Faculty of Medicine Enhanced New Staff Start-up Fund.

6.
Cell ; 184(18): 4784-4818.e17, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450027

RESUMO

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

8.
Mol Psychiatry ; 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193973

RESUMO

Schizophrenia (SCZ) is a debilitating neuropsychiatric disorder with high heritability and complex inheritance. In the past decade, successful identification of numerous susceptibility loci has provided useful insights into the molecular etiology of SCZ. However, applications of these findings to clinical classification and diagnosis, risk prediction, or intervention for SCZ have been limited, and elucidating the underlying genomic and molecular mechanisms of SCZ is still challenging. More recently, multiple Omics technologies - genomics, transcriptomics, epigenomics, proteomics, metabolomics, connectomics, and gut microbiomics - have all been applied to examine different aspects of SCZ pathogenesis. Integration of multi-Omics data has thus emerged as an approach to provide a more comprehensive view of biological complexity, which is vital to enable translation into assessments and interventions of clinical benefit to individuals with SCZ. In this review, we provide a broad survey of the single-omics studies of SCZ, summarize the advantages and challenges of different Omics technologies, and then focus on studies in which multiple omics data are integrated to unravel the complex pathophysiology of SCZ. We believe that integration of multi-Omics technologies would provide a roadmap to create a more comprehensive picture of interactions involved in the complex pathogenesis of SCZ, constitute a rich resource for elucidating the potential molecular mechanisms of the illness, and eventually improve clinical assessments and interventions of SCZ to address clinical translational questions from bench to bedside.

10.
Nat Commun ; 12(1): 3684, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140495

RESUMO

Interaction between tumor cells and immune cells in the tumor microenvironment is important in cancer development. Immune cells interact with the tumor cells to shape this process. Here, we use single-cell RNA sequencing analysis to delineate the immune landscape and tumor heterogeneity in a cohort of patients with HBV-associated human hepatocellular carcinoma (HCC). We found that tumor-associated macrophages suppress tumor T cell infiltration and TIGIT-NECTIN2 interaction regulates the immunosuppressive environment. The cell state transition of immune cells towards a more immunosuppressive and exhaustive status exemplifies the overall cancer-promoting immunocellular landscape. Furthermore, the heterogeneity of global molecular profiles reveals co-existence of intra-tumoral and inter-tumoral heterogeneity, but is more apparent in the latter. This analysis of the immunosuppressive landscape and intercellular interactions provides mechanistic information for the design of efficacious immune-oncology treatments in hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/imunologia , Regulação da Expressão Gênica/imunologia , Neoplasias Hepáticas/imunologia , Macrófagos/imunologia , Microambiente Tumoral/imunologia , Algoritmos , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Proliferação de Células , Regulação da Expressão Gênica/genética , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nectinas/genética , Nectinas/metabolismo , Análise de Componente Principal , Prognóstico , RNA-Seq , Receptores Imunológicos/metabolismo , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral/genética
11.
Bioinformatics ; 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34050728

RESUMO

MOTIVATION: Currently, most genome-wide association studies (GWAS) are studies of a single disease against controls. However, an individual is often affected by more than one condition. For example, coronary artery disease (CAD) is often comorbid with type 2 diabetes (T2DM). Similarly, it is clinically meaningful to study patients with one disease but without a related comorbidity. For example, obese T2DM may have different pathophysiology from non-obese T2DM. RESULTS: We developed a statistical framework (CombGWAS) to uncover susceptibility variants for comorbid disorders (or a disorder without comorbidity), using GWAS summary statistics only. In essence, we mimicked a case-control GWAS in which the cases are affected with comorbidities or a disease without comorbidity. We extended our methodology to analyze continuous traits with clinically meaningful categories (e.g. lipids), and combination of more than 2 traits.We verified the feasibility and validity of our method by applying it to simulated scenarios and four cardiometabolic (CM) traits. In total, we identified 384 and 587 genomic risk loci respectively for 6 comorbidities and 12 CM disease 'subtypes' without a relevant comorbidity. Genetic correlation analysis revealed that some subtypes may be biologically distinct from others. Further Mendelian randomization analysis showed differential causal effects of different subtypes to relevant complications. For example, we found that obese T2DM is causally related to increased risk of CAD (p=2.62E-11). AVAILABILITY: The R code is available at: https://github.com/LiangyingYin/CombGWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

12.
Front Neurosci ; 15: 649588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986640

RESUMO

Background: Recent findings indicated a high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), as well as shared genetic influences on them. The latter might contribute at least partly to the former clinical scenario. This study aimed at investigating whether SHANK genes were potential pleiotropic genes to the two said disorders, underlying their genetic overlap. Methods: This study recruited 298 boys with ADHD (including 256 family trios of 1 ADHD boy and his 2 biological parents), 134 boys with ASD, 109 boys with both ADHD and ASD, and 232 typically developing boys as community controls. They were aged between 6 and 11 years old. Results: There was no significant difference in allele frequency of a number of single nucleotide polymorphisms (SNPs) in SHANK2/SHANK3 between the three clinical groups (ADHD, ASD, and ADHD + ASD) and between the two control groups (community controls and pseudo-controls), respectively. The three clinical groups and the two control groups were thus, respectively, combined. A comparison between the two aggregated samples identified significant evidence of disease association for three SHANK2 SNPs with both ADHD and ASD, even after multiple testing correction: rs11236616 (OR = 0.762, permuted p = 0.0376), rs7106631 (OR = 0.720, permuted p = 0.0034), and rs9888288 (OR = 0.770, permuted p = 0.0407). Comparisons among individual groups pointed to a similar trend of findings. Conclusion: SHANK2 could be considered a potential pleiotropic gene underlying the genetic overlap between ADHD and ASD. This might contribute partly to their high comorbidity in the afflicted children.

13.
Hum Mol Genet ; 30(9): 836-842, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33693786

RESUMO

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (ß = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.

14.
Behav Genet ; 51(3): 215-222, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33630212

RESUMO

Genetic effects on the liability scale are informative for describing the genetic architecture of binary traits, typically diseases. However, most genetic association analyses on binary traits are performed by logistic regression, and there is no straightforward method that transforms both effect size estimate and standard error from the logit scale to the liability scale. Here, we derive a simple linear transformation of the log odds ratio and its standard error for a single nucleotide polymorphism (SNP) to an effect size and standard error on the liability scale. We show by analytic calculations and simulations that this approximation is accurate when the disease is common and the SNP effect is small. We also apply this method to estimate the contribution of a SNP near the RET gene to the variance of Hirschsprung disease liability, and the age-specific contributions of APOE4 on the variance of Alzheimer's disease liability. We discuss the approximate linear inter-relationships between genotype and effect sizes on the observed binary, logit, and liability scales, and the potential applications of the linear approximation to statistical power calculation for binary traits.


Assuntos
Estatística como Assunto/métodos , Testes Genéticos , Genótipo , Humanos , Modelos Logísticos , Modelos Genéticos , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Tamanho da Amostra
15.
Bioinformatics ; 37(13): 1915-1917, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-33270826

RESUMO

SUMMARY: Sampling of control variants having matched properties with input variants is widely used in enrichment analysis of genome-wide association studies/quantitative trait loci and negative data construction for pathogenic/regulatory variant prediction methods. Spurious enrichment results because of confounding factors, such as minor allele frequency and linkage disequilibrium pattern, can be avoided by calibration of statistical significance based on matched controls. Here, we presented vSampler which can generate sets of randomly drawn variants with comprehensive choices of matching properties, such as tissue/cell type-specific epigenomic features. Importantly, the development of a novel data structure and sampling algorithms for vSampler makes it significantly fast than existing tools. AVAILABILITY AND IMPLEMENTATION: vSampler web server and local program are available at http://mulinlab.org/vsampler. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Estudo de Associação Genômica Ampla , Software , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
16.
Oncogene ; 40(6): 1147-1161, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33323975

RESUMO

Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3'-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Transporte/genética , Neoplasias Hepáticas/genética , Fatores de Transcrição NFATC/genética , Transativadores/genética , Proteínas Virais Reguladoras e Acessórias/genética , Animais , Apoptose , Carcinogênese/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Reprogramação Celular/genética , Glicólise/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/genética , Hepatite B Crônica/metabolismo , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Transcriptoma
17.
Psychol Med ; : 1-12, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33032663

RESUMO

BACKGROUND: Depression and cardiovascular disease (CVD) are associated with each other but their relationship remains unclear. We aim to determine whether genetic predisposition to depression are causally linked to CVD [including coronary artery disease (CAD), myocardial infarction (MI), stroke and atrial fibrillation (AF)]. METHODS: Using summary statistics from the largest genome-wide association studies (GWAS) or GWAS meta-analysis of depression (primary analysis: n = 500 199), broad depression (help-seeking behavior for problems with nerves, anxiety, tension or depression; secondary analysis: n = 322 580), CAD (n = 184 305), MI (n = 171 875), stroke (n = 446 696) and AF (n = 1 030 836), genetic correlation was tested between two depression phenotypes and CVD [MI, stroke and AF (not CAD as its correlation was previously confirmed)]. Causality was inferred between correlated traits by Mendelian Randomization analyses. RESULTS: Both depression phenotypes were genetically correlated with MI (depression: rG = 0.169; p = 9.03 × 10-9; broad depression: rG = 0.123; p = 1 × 10-4) and AF (depression: rG = 0.112; p = 7.80 × 10-6; broad depression: rG = 0.126; p = 3.62 × 10-6). Genetically doubling the odds of depression was causally associated with increased risk of CAD (OR = 1.099; 95% CI 1.031-1.170; p = 0.004) and MI (OR = 1.146; 95% CI 1.070-1.228; p = 1.05 × 10-4). Adjustment for blood lipid levels/smoking status attenuated the causality between depression and CAD/MI. Null causal association was observed for CVD on depression. A similar pattern of results was observed in the secondary analysis for broad depression. CONCLUSIONS: Genetic predisposition to depression may have positive causal roles on CAD/MI. Genetic susceptibility to self-awareness of mood problems may be a strong causal risk factor of CAD/MI. Blood lipid levels and smoking may potentially mediate the causal pathway. Prevention and early diagnosis of depression are important in the management of CAD/MI.

18.
Genome Res ; 30(12): 1789-1801, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33060171

RESUMO

The advances of large-scale genomics studies have enabled compilation of cell type-specific, genome-wide DNA functional elements at high resolution. With the growing volume of functional annotation data and sequencing variants, existing variant annotation algorithms lack the efficiency and scalability to process big genomic data, particularly when annotating whole-genome sequencing variants against a huge database with billions of genomic features. Here, we develop VarNote to rapidly annotate genome-scale variants in large and complex functional annotation resources. Equipped with a novel index system and a parallel random-sweep searching algorithm, VarNote shows substantial performance improvements (two to three orders of magnitude) over existing algorithms at different scales. It supports both region-based and allele-specific annotations and introduces advanced functions for the flexible extraction of annotations. By integrating massive base-wise and context-dependent annotations in the VarNote framework, we introduce three efficient and accurate pipelines to prioritize the causal regulatory variants for common diseases, Mendelian disorders, and cancers.

19.
Sci Adv ; 6(42)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33055159

RESUMO

Cardiovascular dysfunction is one of the most common complications of long-term cancer treatment. Growing evidence has shown that antineoplastic drugs can increase cardiovascular risk during cancer therapy, seriously affecting patient survival. However, little is known about the genetic factors associated with the cardiovascular risk of antineoplastic drugs. We established a compendium of genetic evidence that supports cardiovascular risk induced by antineoplastic drugs. Most of this genetic evidence is attributed to causal alleles altering the expression of cardiovascular disease genes. We found that antineoplastic drugs predicted to induce cardiovascular risk are significantly enriched in drugs associated with cardiovascular adverse reactions, including many first-line cancer treatments. Functional experiments validated that retinoid X receptor agonists can reduce triglyceride lipolysis, thus modulating cardiovascular risk. Our results establish a link between the causal allele of cardiovascular disease genes and the direction of pharmacological modulation, which could facilitate cancer drug discovery and clinical trial design.

20.
Genome Res ; 30(11): 1618-1632, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32948616

RESUMO

It is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage-specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain.

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