A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level

EUROSPAN Consortium, Cristian Pattaro, Alessandro De Grandi, Veronique Vitart, Caroline Hayward, Andre Franke, Yurii S. Aulchenko, Asa Johansson, Sarah H. Wild, Scott A. Melville, Aaron Isaacs, Ozren Polasek, David Ellinghaus, Ivana Kolcic, Ute Noethlings, Lina Zgaga, Tatijana Zemunik, Carsten Gnewuch, Stefan Schreiber, Susan CampbellNick Hastie, Mladen Boban, Thomas Meitinger, Ben A. Oostra, Peter Riegler, Cosetta Minelli, Alan F. Wright, Harry Campbell, Cornelia M. van Duijn, Ulf Gyllensten, James F. Wilson, Michael Krawczak, Igor Rudan, Peter P. Pramstaller

Research output: Contribution to journalArticlepeer-review


Background: Serum creatinine (S-CR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in SCR level is explicable by genetic factors.

Methods: We performed a meta-analysis of genome-wide association studies of SCR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR (candidate loci) were replicated in two additional population-based samples ('replication cohorts').

Results: After the discovery meta-analysis, 29 loci were selected for replication. Association between SCR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 x 10(-6) and 1.7 x 10(-4), respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 x 10(-3)). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated.

Conclusions: While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABA(A) receptors in the regulation of the glomerular basement membrane and a possible interaction between GABA(A)receptors and synaptotagmin-I at the podocyte level.

Original languageEnglish
Pages (from-to)-
Number of pages17
JournalBMC Medical Genetics
Issue number41
Publication statusPublished - 11 Mar 2010


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