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MicroRNAs enrichment in GWAS of complex human phenotypes.

ABSTRACT: The genotype information carried by Genome-wide association studies (GWAS) seems to have the potential to explain more of the 'missing heritability' of complex human phenotypes, given improved statistical approaches. Several lines of evidence support the involvement of microRNA (miRNA) and other non-coding RNA in complex human traits and diseases. We employed a novel, genetic annotation-informed enrichment method for GWAS that captures more polygenic effects than standard GWAS analysis, to investigate if miRNA-tagging Single Nucleotide Polymorphisms (SNPs) are enriched of associations with 15 complex human phenotypes. We then leveraged the enrichment using a conditional False Discovery Rate (condFDR) approach to assess any improvement in the detection of individual miRNA SNPs associated with the disorders.We found SNPs tagging miRNA transcription regions to be significantly enriched of associations with 10 of 15 phenotypes. The enrichment remained significant after controlling for affiliation to other genomic categories, and was confirmed by replication. Albeit only nominally significant, enrichment was found also in miRNA binding sites for 10 phenotypes out of 15. Leveraging the enrichment in the condFDR framework, we observed a 2-4-fold increase in discovery of SNPs tagging miRNA regions.Our results suggest that miRNAs play an important role in the polygenic architecture of complex human disorders and traits, and therefore that miRNAs are a genomic category that can and should be used to improve gene discovery.

SUBMITTER: Goulart LF

PROVIDER: S-EPMC4437677 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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MicroRNAs enrichment in GWAS of complex human phenotypes.

Goulart Luiz F LF Bettella Francesco F Sønderby Ida E IE Schork Andrew J AJ Thompson Wesley K WK Mattingsdal Morten M Steen Vidar M VM Zuber Verena V Wang Yunpeng Y Dale Anders M AM Andreassen Ole A OA Djurovic Srdjan S

BMC genomics 20150416

<h4>Background</h4>The genotype information carried by Genome-wide association studies (GWAS) seems to have the potential to explain more of the 'missing heritability' of complex human phenotypes, given improved statistical approaches. Several lines of evidence support the involvement of microRNA (miRNA) and other non-coding RNA in complex human traits and diseases. We employed a novel, genetic annotation-informed enrichment method for GWAS that captures more polygenic effects than standard GWAS ...[more]

PMID: 25884492

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Project description:BackgroundNeuroblastoma (NB) is the most common extracranial solid tumor in children. NB tumors and derived cell lines are phenotypically heterogeneous. Cell lines are classified by phenotype, each having distinct differentiation and tumorigenic properties. The neuroblastic phenotype is tumorigenic, has neuronal features and includes stem cells (I-cells) and neuronal cells (N-cells). The non-neuronal phenotype (S-cell) comprises cells that are non-tumorigenic with features of glial/smooth muscle precursor cells. This study identified miRNAs associated with each distinct cell phenotypes and investigated their role in regulating associated differentiation and tumorigenic properties.MethodsA miRNA microarray was performed on the three cell phenotypes and expression verified by qRT-PCR. miRNAs specific for certain cell phenotypes were modulated using miRNA inhibitors or stable transfection. Neuronal differentiation was induced by RA; non-neuronal differentiation by BrdU. Changes in tumorigenicity were assayed by soft agar colony forming ability. N-myc binding to miR-375 promoter was assayed by chromatin-immunoprecipitation.ResultsUnsupervised hierarchical clustering of miRNA microarray data segregated neuroblastic and non-neuronal cell lines and showed that specific miRNAs define each phenotype. qRT-PCR validation confirmed that increased levels of miR-21, miR-221 and miR-335 are associated with the non-neuronal phenotype, whereas increased levels of miR-124 and miR-375 are exclusive to neuroblastic cells. Downregulation of miR-335 in non-neuronal cells modulates expression levels of HAND1 and JAG1, known modulators of neuronal differentiation. Overexpression of miR-124 in stem cells induces terminal neuronal differentiation with reduced malignancy. Expression of miR-375 is exclusive for N-myc-expressing neuroblastic cells and is regulated by N-myc. Moreover, miR-375 downregulates expression of the neuronal-specific RNA binding protein HuD.ConclusionsThus, miRNAs define distinct NB cell phenotypes. Increased levels of miR-21, miR-221 and miR-335 characterize the non-neuronal, non-malignant phenotype and miR-335 maintains the non-neuronal features possibly by blocking neuronal differentiation. miR-124 induces terminal neuronal differentiation with reduction in malignancy. Data suggest N-myc inhibits neuronal differentiation of neuroblastic cells possibly by upregulating miR-375 which, in turn, suppresses HuD. As tumor differentiation state is highly predictive of patient survival, the involvement of these miRNAs with NB differentiation and tumorigenic state could be exploited in the development of novel therapeutic strategies for this enigmatic childhood cancer.

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MicroRNAs enrichment in GWAS of complex human phenotypes.

Publications

MicroRNAs enrichment in GWAS of complex human phenotypes.

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