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Original research
Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways
  1. William Schierding1,
  2. Julia A Horsfield2,3,
  3. Justin M O'Sullivan1,3,4
  1. 1Liggins Institute, The University of Auckland, Auckland, New Zealand
  2. 2Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
  3. 3Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
  4. 4MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, Hampshire, UK
  1. Correspondence to Dr William Schierding, The University of Auckland Liggins Institute, Auckland 1142, New Zealand; w.schierding{at}; Dr Julia A Horsfield, Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; julia.horsfield{at}


Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested.

Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed).

Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function.

Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.

  • molecular biology
  • genetic association studies
  • human genetics
  • genetic predisposition to disease
  • gene expression regulation

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  • Contributors WS planned the study and performed analyses. WS and JAH drafted the manuscript. All authors analysed data, revised the manuscript and approved the final version.

  • Funding This work was supported by a Royal Society of New Zealand Marsden Grant to JAH and JO (16-UOO-072), and WS was supported by the same grant.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All raw data used for this paper is available from publically available datasets, with appropriate URLs and citations placed in the relevant methods sections in the manuscript.

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