Draaken Markus, Knapp Michael, Pennimpede Tracie, Schmidt Johanna M, Ebert Anne-Karolin, Rösch Wolfgang, Stein Raimund, Utsch Boris, Hirsch Karin, Boemers Thomas M, Mangold Elisabeth, Heilmann Stefanie, Ludwig Kerstin U, Jenetzky Ekkehart, Zwink Nadine, Moebus Susanne, Herrmann Bernhard G, Mattheisen Manuel, Nöthen Markus M, Ludwig Michael, Reutter Heiko
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
PLoS Genet. 2015 Mar 12;11(3):e1005024. doi: 10.1371/journal.pgen.1005024. eCollection 2015 Mar.
The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10-12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.
膀胱外翻-尿道上裂复合畸形（BEEC）代表泌尿直肠畸形谱系的严重末端，被认为是泄殖腔膜和泌尿直肠隔异常胚胎形态发生的结果。BEEC最常见的形式是孤立性经典膀胱外翻（CBE）。为了确定CBE的易感基因座，我们对110例CBE患者和1177例欧洲裔对照进行了全基因组关联研究（GWAS）。在此，发现与5号染色体q11.1上一个约220kb的区域存在关联。该区域包含ISL1（ISL LIM同源框1）基因。该区域的多个标记显示出与CBE相关的证据，包括84个具有全基因组显著性的标记。然后，我们使用我们小组之前对98例CBE患者和526例欧洲裔对照进行的GWAS数据进行了荟萃分析。该荟萃分析也表明5q11.1基因座与CBE风险有关。在荟萃分析中，该基因座共有138个标记达到全基因组显著性，最显著的标记（rs9291768）的P值为2.13×10-12。荟萃分析中的其他基因座均未达到全基因组显著性。然后，我们进行了小鼠表达分析以跟进这一发现。在此，在人类CBE发育的关键时间框架内，在生殖区域检测到了Isl1表达。表达Isl1的生殖区域包括泄殖腔周围间充质和泌尿直肠隔。本研究在染色体区域5q11.1上确定了首个全基因组显著的CBE基因座，并为ISL1是该区域的致病候选基因这一假说提供了有力证据。
