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1.
Artigo em Inglês | MEDLINE | ID: mdl-31385379

RESUMO

Genetic interaction has been recognized to be an important cause of the missing heritability. The topologically associating domain (TAD) is a self-interacting genomic region, and the DNA sequences within a TAD physically interact with each other more frequently. Sex differences influence cancer susceptibility at the genetic level. Here, we performed both regular and sex-specific genetic interaction analyses within TAD to identify susceptibility genes for lung cancer in 5204 lung cancer patients and 7389 controls. We found that one SNP pair, rs4262299-rs1654701, was associated with lung cancer in women after multiple testing corrections (combined P = 8.52 × 10-9 ). Single-SNP analyses did not detect significant association signals for these two SNPs. Both identified SNPs are located in the intron region of ANGPT1. We further found that 5% of nonsmall cell lung cancer patients have an alteration in ANGPT1, indicated the potential role of ANGPT1 in the neoplastic progression in lung cancer. The expression of ANGPT1 was significantly down-regulated in patients in lung squamous cell carcinoma and lung adenocarcinoma. We checked the interaction effect on the ANGPT1 expression and lung cancer and found that the minor allele "G" of rs1654701 increased ANGPT1 gene expression and decreased lung cancer risk with the increased dosage of "A" of rs4262299, which consistent with the tumor suppressor function of ANGPT1. Survival analyses found that the high expression of ANGPT1 was individually associated with a higher survival probability in lung cancer patients. In summary, our results suggest that ANGPT1 may be a novel tumor suppressor gene for lung cancer.

2.
Transl Psychiatry ; 9(1): 56, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705251

RESUMO

Nearly 95% of susceptibility SNPs identified by genome-wide association studies (GWASs) are located in non-coding regions, which causes a lot of difficulty in deciphering their biological functions on disease pathogenesis. Here, we aimed to conduct a comprehensive functional annotation for all the schizophrenia susceptibility loci obtained from GWASs. Considering varieties of epigenomic regulatory elements, we annotated all 22,688 acquired susceptibility SNPs according to their genomic positions to obtain functional SNPs. The comprehensive annotation indicated that these functional SNPs are broadly involved in diverse biological processes. Histone modification enrichment showed that H3K27ac, H3K36me3, H3K4me1, and H3K4me3 were related to the development of schizophrenia. Transcription factors (TFs) prediction, methylation quantitative trait loci (meQTL) analyses, expression quantitative trait loci (eQTL) analyses, and proteomic quantitative trait loci analyses (pQTL) identified 447 target protein-coding genes. Subsequently, differential expression analyses between schizophrenia cases and controls, nervous system phenotypes from mouse models, and protein-protein interaction with known schizophrenia-related pathways and genes were carried out with our target genes. We finaly prioritized 10 target genes for schizophrenia (CACNA1C, CLU, CSNK2B, GABBR1, GRIN2A, MAPK3, NOTCH4, SRR, TNF, and SYNGAP1). Our results may serve as an encyclopedia of schizophrenia susceptibility SNPs and offer holistic guides for post-GWAS functional experiments.


Assuntos
Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Metilação de DNA , Epigênese Genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Código das Histonas , Histonas/genética , Humanos , Rombencéfalo/metabolismo , Esquizofrenia/metabolismo
3.
Int J Obes (Lond) ; 43(3): 450-456, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29717274

RESUMO

BACKGROUND: Genome-wide association studies have identified many susceptibility loci for obesity. However, missing heritability problem is still challenging and ignorance of genetic interactions is believed to be an important cause. Current methods for detecting interactions usually do not consider regulatory elements in non-coding regions. Interaction analyses within chromatin regulatory circuitry may identify new susceptibility loci. METHODS: We developed a pipeline named interaction analyses within chromatin regulatory circuitry (IACRC), to identify genetic interactions impacting body mass index (BMI). Potential interacting SNP pairs were obtained based on Hi-C datasets, PreSTIGE (Predicting Specific Tissue Interactions of Genes and Enhancers) algorithm, and super enhancer regions. SNP × SNP analyses were next performed in three GWAS datasets, including 2286 unrelated Caucasians from Kansas City, 3062 healthy Caucasians from the Gene Environment Association Studies initiative, and 3164 Hispanic subjects from the Women's Health Initiative. RESULTS: A total of 16,643,227 SNP × SNP analyses were performed. Meta-analyses showed that two SNP pairs, rs6808450-rs9813534 (combined P = 2.39 × 10-9) and rs6808450-rs3773306 (combined P = 2.89 × 10-9) were associated with BMI after multiple testing corrections. Single-SNP analyses did not detect significant association signals for these three SNPs. In obesity relevant cells, rs6808450 is located in intergenic enhancers, while rs9813534 and rs3773306 are located in the region of strong transcription regions of CAND2 and RPL32, respectively. The expression of CAND2 was significantly downregulated after the differentiation of human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cells (P = 0.0241). Functional validation in the International Mouse Phenotyping Consortium database showed that CAND2 was associated with increased lean body mass and decreased total body fat amount. CONCLUSIONS: Detecting epistasis within chromatin regulatory circuitry identified CAND2 as a novel obesity susceptibility gene. We hope IACRC could facilitate the interaction analyses for complex diseases and offer new insights into solving the missing heritability problem.


Assuntos
Epistasia Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas Musculares/genética , Obesidade , Fatores de Transcrição/genética , Adulto , Idoso , Índice de Massa Corporal , Cromatina/genética , Humanos , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética
4.
Brief Bioinform ; 20(1): 26-32, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28968709

RESUMO

Genome-wide association studies (GWASs) are an effective strategy to identify susceptibility loci for human complex diseases. However, missing heritability is still a big problem. Most GWASs single-nucleotide polymorphisms (SNPs) are located in noncoding regions, which has been considered to be the unexplored territory of the genome. Recently, data from the Encyclopedia of DNA Elements (ENCODE) and Roadmap Epigenomics projects have shown that many GWASs SNPs in the noncoding regions fall within regulatory elements. In this study, we developed a pipeline named functional disease-associated SNPs prediction (FDSP), to identify novel susceptibility loci for complex diseases based on the interpretation of the functional features for known disease-associated variants with machine learning. We applied our pipeline to predict novel susceptibility SNPs for type 2 diabetes (T2D) and hypertension. The predicted SNPs could explain heritability beyond that explained by GWAS-associated SNPs. Functional annotation by expression quantitative trait loci analyses showed that the target genes of the predicted SNPs were significantly enriched in T2D or hypertension-related pathways in multiple tissues. Our results suggest that combining GWASs and regulatory features data could identify additional functional susceptibility SNPs for complex diseases. We hope FDSP could help to identify novel susceptibility loci for complex diseases and solve the missing heritability problem.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Software , Algoritmos , Biologia Computacional , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Humanos , Hipertensão/genética , Aprendizado de Máquina , Modelos Genéticos , Modelos Estatísticos , Herança Multifatorial , Locos de Características Quantitativas , Sequências Reguladoras de Ácido Nucleico
5.
J Cancer ; 9(21): 3858-3866, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30410588

RESUMO

Although genome-wide association studies (GWASs) have identified some risk single-nucleotide polymorphisms in East Asian never-smoking females, the unexplained missing heritability is still required to be investigated. Runs of homozygosity (ROHs) are thought to be a type of genetic variation acting on human complex traits and diseases. We detected ROHs in 8,881 East Asian never-smoking women. The summed ROHs were used to fit a logistic regression model which noteworthily revealed a significant association between ROHs and the decreased risk of lung cancer (P < 0.05). We identified 4 common ROHs regions located at 2p22.1, which were significantly associated with decreased risk of lung cancer (P = 2.00 × 10-4 - 1.35 × 10-4). Functional annotation was conducted to investigate the regulatory function of ROHs. The common ROHs were overlapped with potential regulatory elements, such as active epigenome elements and chromatin states in lung-derived cell lines. SOS1 and ARHGEF33 were significantly up-regulated as the putative target genes of the identified ROHs in lung cancer samples according to the analysis of differently expressed genes. Our results suggest that ROHs could act as recessive contributing factors and regulatory elements to influence the risk of lung cancer in never-smoking East Asian females.

6.
Am J Hum Genet ; 102(5): 776-793, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29706346

RESUMO

Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis.


Assuntos
Alelos , Cromossomos Humanos Par 1/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Conformação de Ácido Nucleico , Osteoporose/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Densidade Óssea/genética , Osso e Ossos/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular , Cromatina/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Regiões Promotoras Genéticas , Ligação Proteica , Locos de Características Quantitativas/genética , RNA Longo não Codificante/química , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Transcrição/metabolismo
7.
J Bone Miner Res ; 33(7): 1335-1346, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29528523

RESUMO

RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genomewide association studies (GWASs) have identified multiple intergenic single-nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (high-throughput chromosome conformation capture [Hi-C]), epigenetic annotation, and a series of functional assays. The eQTL analysis identified six potential functional SNPs (rs9533090, rs9594738, r8001611, rs9533094, rs9533095, and rs9594759) exclusively correlated with RANKL gene expression (p < 0.001) at 13q14.11. Co-localization analyses suggested that eQTL signal for RANKL and BMD-GWAS signal shared the same causal variants. Hi-C analysis and functional annotation further validated that the first five osteoporosis SNPs are located in a super-enhancer region to regulate the expression of RANKL via long-range chromosomal interaction. Particularly, dual-luciferase assay showed that the region harboring rs9533090 in the super-enhancer has the strongest enhancer activity, and rs9533090 is an allele-specific regulatory SNP. Furthermore, deletion of the region harboring rs9533090 using CRISPR/Cas9 genome editing significantly reduced RANKL expression in both mRNA level and protein level. Finally, we found that the rs9533090-C robustly recruits transcription factor NFIC, which efficiently elevates the enhancer activity and increases the RANKL expression. In summary, we provided a feasible method to identify regulatory noncoding SNPs to distally regulate their target gene underlying the pathogenesis of osteoporosis by using bioinformatics data analyses and experimental validation. Our findings would be a potential and promising therapeutic target for precision medicine in osteoporosis. © 2018 American Society for Bone and Mineral Research.


Assuntos
Cromossomos Humanos Par 13/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Osteoporose/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Ligante RANK/genética , Alelos , Densidade Óssea/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Cromatina/genética , Humanos , Modelos Genéticos , Anotação de Sequência Molecular , Fatores de Transcrição NFI/metabolismo , Mapeamento Físico do Cromossomo , Ligação Proteica , Reprodutibilidade dos Testes , Fatores de Risco
8.
Hum Genet ; 136(8): 963-974, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28634715

RESUMO

Despite genome-wide association studies (GWASs) have identified many susceptibility genes for osteoporosis, it still leaves a large part of missing heritability to be discovered. Integrating regulatory information and GWASs could offer new insights into the biological link between the susceptibility SNPs and osteoporosis. We generated five machine learning classifiers with osteoporosis-associated variants and regulatory features data. We gained the optimal classifier and predicted genome-wide SNPs to discover susceptibility regulatory variants. We further utilized Genetic Factors for Osteoporosis Consortium (GEFOS) and three in-house GWASs samples to validate the associations for predicted positive SNPs. The random forest classifier performed best among all machine learning methods with the F1 score of 0.8871. Using the optimized model, we predicted 37,584 candidate SNPs for osteoporosis. According to the meta-analysis results, a list of regulatory variants was significantly associated with osteoporosis after multiple testing corrections and contributed to the expression of known osteoporosis-associated protein-coding genes. In summary, combining GWASs and regulatory elements through machine learning could provide additional information for understanding the mechanism of osteoporosis. The regulatory variants we predicted will provide novel targets for etiology research and treatment of osteoporosis.


Assuntos
Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Algoritmos , Linhagem Celular , Galanina/genética , Galanina/metabolismo , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Separase/genética , Separase/metabolismo
9.
PLoS One ; 7(11): e49711, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23185415

RESUMO

The nuclear factor-kappa B (NF-κB) pathways play important roles in innate immune responses. IκB is the main cytoplasmic inhibitor of NF-κB. In this study, we identified the LvCactus gene from Litopenaeus vannamei, which is the first cloned IκB homologue in subphylum Crustacea. LvCactus contains six predicted ankyrin repeats, which show similarities to those of Cactus proteins from insects. LvCactus localizes in cytoplasm and interacts with LvDorsal, an L. vannamei homologue to Drosophila melanogaster Dorsal belonging to class II NF-κB family, to prevent its nuclear translocation. Contrary to that of LvDorsal, over-expression of LvCactus down-regulates the activities of shrimp antimicrobial peptides promoters, suggesting LvCactus is an inhibitor of LvDorsal. The promoter of LvCactus was predicted to contain five putative NF-κB binding motifs, among which four were proved to be bound by LvDorsal by chromatin immunoprecipitation assays. Dual-luciferase reporter assays also showed that transcription of LvCactus was promoted by LvDorsal but inhibited by LvCactus itself, indicating a feedback regulatory pathway between LvCactus and LvDorsal. Expression of LvCactus was up-regulated after Lipopolysaccharides, poly (I:C), Vibrio parahaemolyticus, and Staphylococcus aureus injections, suggesting an activation response of LvCactus to bacterial and immune stimulant challenges. Differently, the LvCactus expression levels obviously decreased during white spot syndrome virus (WSSV) infection, indicating the feedback regulatory pathway of LvCactus/LvDorsal could be modified by WSSV.


Assuntos
Regulação da Expressão Gênica , Penaeidae/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Clonagem Molecular , Biologia Computacional/métodos , DNA Complementar/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Genoma , Proteínas I-kappa B/metabolismo , Imunoprecipitação , Microscopia Confocal/métodos , Dados de Sequência Molecular , Fosfoproteínas/genética , Filogenia , Homologia de Sequência de Aminoácidos , Especificidade da Espécie
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