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Leveraging cross-species transcription factor binding site patterns: from diabetes risk Loci to disease mechanisms.

Claussnitzer, Melina; Dankel, Simon N; Klocke, Bernward; Grallert, Harald; Glunk, Viktoria; Berulava, Tea; Lee, Heekyoung; Oskolkov, Nikolay LU ; Fadista, Joao LU and Ehlers, Kerstin, et al. (2014) In Cell 156(1-2). p.343-358
Abstract
Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2... (More)
Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms. (Less)
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Contribution to journal
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in
Cell
volume
156
issue
1-2
pages
343 - 358
publisher
Cell Press
external identifiers
  • wos:000329912200032
  • pmid:24439387
  • scopus:84892689100
ISSN
1097-4172
DOI
10.1016/j.cell.2013.10.058
language
English
LU publication?
yes
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ab111aca-769a-4d9f-92c5-9231ec557d24 (old id 4291144)
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http://www.ncbi.nlm.nih.gov/pubmed/24439387?dopt=Abstract
date added to LUP
2014-02-07 22:56:18
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2017-11-19 03:08:38
@article{ab111aca-769a-4d9f-92c5-9231ec557d24,
  abstract     = {Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.},
  author       = {Claussnitzer, Melina and Dankel, Simon N and Klocke, Bernward and Grallert, Harald and Glunk, Viktoria and Berulava, Tea and Lee, Heekyoung and Oskolkov, Nikolay and Fadista, Joao and Ehlers, Kerstin and Wahl, Simone and Hoffmann, Christoph and Qian, Kun and Rönn, Tina and Riess, Helene and Müller-Nurasyid, Martina and Bretschneider, Nancy and Schroeder, Timm and Skurk, Thomas and Horsthemke, Bernhard and Spieler, Derek and Klingenspor, Martin and Seifert, Martin and Kern, Michael J and Mejhert, Niklas and Dahlman, Ingrid and Hansson, Ola and Hauck, Stefanie M and Blüher, Matthias and Arner, Peter and Groop, Leif and Illig, Thomas and Suhre, Karsten and Hsu, Yi-Hsiang and Mellgren, Gunnar and Hauner, Hans and Laumen, Helmut},
  issn         = {1097-4172},
  language     = {eng},
  number       = {1-2},
  pages        = {343--358},
  publisher    = {Cell Press},
  series       = {Cell},
  title        = {Leveraging cross-species transcription factor binding site patterns: from diabetes risk Loci to disease mechanisms.},
  url          = {http://dx.doi.org/10.1016/j.cell.2013.10.058},
  volume       = {156},
  year         = {2014},
}