Genome supranucleosomal organization and genetic susceptibility to diseases

Jablonski, Kim Philipp; Fretter, Christoph; Carron, Leopold; Forné, Thierry; Hütt, Marc‐Thorsten; Lesne, Annick

doi:10.1063/1.5001606

Cited by 3 publications

(7 citation statements)

References 71 publications

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“…Our analysis shows that for a fraction of diseases, their associated SNPs are preferentially located in TAD borders, as already observed in a preliminary study [26]. A recent study centered on complex trait heritability consistently put forward a specific status of TAD borders [48].…”

Section: For a Fraction Of Diseases Their Associated Snps Are Preferentially Located In Tad Borderssupporting

confidence: 83%

“…Different cell types and data obtained in different laboratories have been considered (overall 15 datasets). Based on a preliminary analysis [26] and on their different etiology, we analyzed separately 71 cancers and 378 non-cancer diseases and compared the distribution of their associated SNPs with respect to TAD borders. We analyzed, for each disease, the distribution of its disease-associated SNPs in TAD borders compared to chance, where chance corresponds to the same number of pointwise loci drawn at random either in the entire genome or in the set of SNPs listed in the GWAS catalog.…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted July 27, 2021. ; https://doi.org/10.1101/2021.07. 26.453813 doi: bioRxiv preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

mentioning

confidence: 99%

“…The copyright holder for this preprint this version posted July 27, 2021. ; https://doi.org/10.1101/2021.07. 26.453813 doi: bioRxiv preprint…”

mentioning

confidence: 99%

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Contribution of 3D genome topological domains to genetic risk of cancers

Jablonski

Carron

Mozziconacci

et al. 2021

Preprint

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Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in 3-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically-associating domains (TADs) and their borders. For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e. the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases display such a preferential location of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that TAD border enrichment in risk loci differ between cancers and non-cancer diseases. Different TAD border enrichments are observed in embryonic stem cells and differentiated cells, which agrees with an evolution along embryogenesis of the 3D genome organization into topological domains. Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically-insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with a direct effect on an individual gene, the other acting in interplay with 3D genome organization.

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Section: For a Fraction Of Diseases Their Associated Snps Are Preferentially Located In Tad Borderssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

“…The copyright holder for this preprint this version posted July 27, 2021. ; https://doi.org/10.1101/2021.07. 26.453813 doi: bioRxiv preprint…”

mentioning

confidence: 99%

See 2 more Smart Citations

Contribution of 3D genome topological domains to genetic risk of cancers

Jablonski

Carron

Mozziconacci

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Our analysis shows that for a fraction of diseases, their associated SNPs are preferentially located in TAD borders, as already observed in a preliminary study [29]. A recent study centered on complex trait heritability consistently put forward a speci c status of TAD borders [32].…”

Section: For a Fraction Of Diseases Their Associated Snps Are Preferentially Located In Tad Borderssupporting

confidence: 82%

Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

Jablonski

Carron²,

Mozziconacci³

et al. 2021

Preprint

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Background Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in 3-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically-associating domains (TADs) and their borders. Results For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e. the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differ between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. Conclusions Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically-insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with a direct effect on an individual gene, the other acting in interplay with 3D genome organization.

show abstract

Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

et al. 2022

View full text Add to dashboard Cite

Background Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders. Results For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. Conclusions Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.

show abstract

Genome supranucleosomal organization and genetic susceptibility to diseases

Cited by 3 publications

References 71 publications

Contribution of 3D genome topological domains to genetic risk of cancers

Contribution of 3D genome topological domains to genetic risk of cancers

Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

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