Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals

Cavalli, Marco; Pan, Gang; Nord, Helena; Arzt, Emelie Wallén; Wallerman, Ola; Wadelius, Claes

doi:10.1016/j.ygeno.2016.04.006

Cited by 19 publications

(27 citation statements)

References 29 publications

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“…Since the ENCODE Project was initiated with the aim to find all functional elements in the genome, it has accumulated numerous data on chromatin and transcribed genes obtained from various cell lines and tissues, and based on these, candidate regulatory SNPs may be found. In particular, available ChIP-seq data on allele-specific binding of different transcription factors (TFs) could be considered as a clear sign that the SNPs with regulatory potential are located within the genome regions occupied by these factors [ 15 – 17 ]. ChIP-seq data on allele-specific binding of active chromatin marks can also provide important insights towards the localization of regulatory variants particularly in combination with allele-specific expression profiles from RNA-seq [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia

et al. 2018

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BackgroundA challenge of understanding the mechanisms underlying cognition including neurodevelopmental and neuropsychiatric disorders is mainly given by the potential severity of cognitive disorders for the quality of life and their prevalence. However, the field has been focused predominantly on protein coding variation until recently. Given the importance of tightly controlled gene expression for normal brain function, the goal of the study was to assess the functional variation including non-coding variation in human genome that is likely to play an important role in cognitive functions. To this end, we organized and utilized available genome-wide datasets from genomic, transcriptomic and association studies into a comprehensive data corpus. We focused on genomic regions that are enriched in regulatory activity—overlapping transcriptional factor binding regions and repurpose our data collection especially for identification of the regulatory SNPs (rSNPs) that showed associations both with allele-specific binding and allele-specific expression. We matched these rSNPs to the nearby and distant targeted genes and then selected the variants that could implicate the etiology of cognitive disorders according to Genome-Wide Association Studies (GWAS). Next, we use DeSeq 2.0 package to test the differences in the expression of the certain targeted genes between the controls and the patients that were diagnosed bipolar affective disorder and schizophrenia. Finally, we assess the potential biological role for identified drivers of cognition using DAVID and GeneMANIA.ResultsAs a result, we selected fourteen regulatory SNPs locating within the loci, implicated from GWAS for cognitive disorders with six of the variants unreported previously. Grouping of the targeted genes according to biological functions revealed the involvement of processes such as ‘posttranscriptional regulation of gene expression’, ‘neuron differentiation’, ‘neuron projection development’, ‘regulation of cell cycle process’ and ‘protein catabolic processes’. We identified four rSNP-targeted genes that showed differential expression between patient and control groups depending on brain region: NRAS—in schizophrenia cohort, CDC25B, DDX21 and NUCKS1—in bipolar disorder cohort.ConclusionsOverall, our findings are likely to provide the keys for unraveling the mechanisms that underlie cognitive functions including major depressive disorder, bipolar disorder and schizophrenia etiopathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0414-3) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

“…Thus, the study of allele-specific events of any kind seems very valuable for identifying the functional regulatory consequences of non-coding SNPs. Notably; these allow analyzing the functionality of a significant amount of SNPs utilizing a relatively small amount of experimental datasets [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia

et al. 2018

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“…The gene that is responsible for a trait may be located relatively far from the GWAS associated SNPs, as the causal SNPs may modulate TF binding and TFs can act distally to regulate gene transcription. In these cases, preferential binding of a TF to one allele causes differential regulation of gene expression to confer the phenotype [ 37 ]. Several studies have provided evidence of causal relationships for gene expression mediating the association between GWAS SNPs and traits [ 16 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of breast cancer associated variants that modulate transcription factor binding

et al. 2017

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Genome-wide association studies (GWAS) have discovered thousands loci associated with disease risk and quantitative traits, yet most of the variants responsible for risk remain uncharacterized. The majority of GWAS-identified loci are enriched for non-coding single-nucleotide polymorphisms (SNPs) and defining the molecular mechanism of risk is challenging. Many non-coding causal SNPs are hypothesized to alter transcription factor (TF) binding sites as the mechanism by which they affect organismal phenotypes. We employed an integrative genomics approach to identify candidate TF binding motifs that confer breast cancer-specific phenotypes identified by GWAS. We performed de novo motif analysis of regulatory elements, analyzed evolutionary conservation of identified motifs, and assayed TF footprinting data to identify sequence elements that recruit TFs and maintain chromatin landscape in breast cancer-relevant tissue and cell lines. We identified candidate causal SNPs that are predicted to alter TF binding within breast cancer-relevant regulatory regions that are in strong linkage disequilibrium with significantly associated GWAS SNPs. We confirm that the TFs bind with predicted allele-specific preferences using CTCF ChIP-seq data. We used The Cancer Genome Atlas breast cancer patient data to identify ANKLE1 and ZNF404 as the target genes of candidate TF binding site SNPs in the 19p13.11 and 19q13.31 GWAS-identified loci. These SNPs are associated with the expression of ZNF404 and ANKLE1 in breast tissue. This integrative analysis pipeline is a general framework to identify candidate causal variants within regulatory regions and TF binding sites that confer phenotypic variation and disease risk.

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“…However, despite its wide usage, its genomic sequence and structural features have never been characterized in a comprehensive manner beyond its karyotype (Simon et al 1982;Chen et al 1993) and SNVs identified from ChIP-Seq data and 10x coverage WGS that do not take aneuploidy or CN into consideration (Huang and Ovcharenko 2015;Cavalli et al 2016). …”

Section: Discussionmentioning

confidence: 99%

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Zhou

Greer

Spies

et al. 2018

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HepG2 is one of the most widely used human cell lines in biomedical research and one of the main cell lines of ENCODE. Although the functional genomic and epigenomic characteristics of HepG2 are extensively studied, its genome sequence has never been comprehensively analyzed and higher-order structural features of its genome beyond its karyotype were only cursorily known. The high degree of aneuploidy in HepG2 renders traditional genome variant analysis methods challenging and partially ineffective. Correct and complete interpretation of the extensive functional genomics data fromHepG2 requires an understanding of the cell line's genome sequence and genome structure. We performed deep whole-genome sequencing, mate-pair sequencing and linked-read sequencing to identify a wide spectrum of genome characteristics in HepG2: copy numbers of chromosomal segments, SNVs and Indels (both corrected for copynumber), phased haplotype blocks, structural variants (SVs) including complex genomic rearrangements, and novel mobile element insertions. A large number of SVs were phased, sequence assembled and experimentally validated. Several chromosomes show striking loss of heterozygosity. We re-analyzed HepG2 RNA-Seq and wholegenome bisulfite sequencing data for allele-specific expression and phased DNA methylation. We show examples where deeper insights into genomic regulatory complexity could be gained by taking knowledge of genomic structural contexts into account. Furthermore, we used the haplotype information to produce an allele-specific CRISPR targeting map. This comprehensive whole-genome analysis serves as a resource for future studies that utilize HepG2.

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Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals

Cited by 19 publications

References 29 publications

Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia

Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia

Identification of breast cancer associated variants that modulate transcription factor binding

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

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