Kristiansen Wenche, Karlsson Robert, Rounge Trine B, Whitington Thomas, Andreassen Bettina K, Magnusson Patrik K, Fosså Sophie D, Adami Hans-Olov, Turnbull Clare, Haugen Trine B, Grotmol Tom, Wiklund Fredrik
Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Hum Mol Genet. 2015 Jul 15;24(14):4138-46. doi: 10.1093/hmg/ddv129. Epub 2015 Apr 15.
Genome-wide association (GWA) studies have reported 19 distinct susceptibility loci for testicular germ cell tumor (TGCT). A GWA study for TGCT was performed by genotyping 610 240 single-nucleotide polymorphisms (SNPs) in 1326 cases and 6687 controls from Sweden and Norway. No novel genome-wide significant associations were observed in this discovery stage. We put forward 27 SNPs from 15 novel regions and 12 SNPs previously reported, for replication in 710 case-parent triads and 289 cases and 290 controls. Predefined biological pathways and processes, in addition to a custom-built sex-determination gene set, were subject to enrichment analyses using Meta-Analysis Gene Set Enrichment of Variant Associations (M) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (I). In the combined meta-analysis, we observed genome-wide significant association for rs7501939 on chromosome 17q12 (OR = 0.78, 95% CI = 0.72-0.84, P = 1.1 × 10(-9)) and rs2195987 on chromosome 19p12 (OR = 0.76, 95% CI: 0.69-0.84, P = 3.2 × 10(-8)). The marker rs7501939 on chromosome 17q12 is located in an intron of the HNF1B gene, encoding a member of the homeodomain-containing superfamily of transcription factors. The sex-determination gene set (false discovery rate, FDRM < 0.001, FDRI < 0.001) and pathways related to NF-κB, glycerophospholipid and ether lipid metabolism, as well as cancer and apoptosis, was associated with TGCT (FDR < 0.1). In addition to revealing two new TGCT susceptibility loci, our results continue to support the notion that genes governing normal germ cell development in utero are implicated in the development of TGCT.
全基因组关联（GWA）研究已报告了19个不同的睾丸生殖细胞肿瘤（TGCT）易感位点。通过对来自瑞典和挪威的1326例病例和6687例对照中的610240个单核苷酸多态性（SNP）进行基因分型，开展了一项针对TGCT的GWA研究。在这个发现阶段未观察到新的全基因组显著关联。我们从15个新区域中提出了27个SNP以及先前报告的12个SNP，在710个病例-父母三联体以及289例病例和290例对照中进行验证。除了一个定制的性别决定基因集外，预定义的生物学途径和过程还使用变异关联的元分析基因集富集（M）和全基因组关联研究的改进基因集富集分析（I）进行了富集分析。在联合元分析中，我们观察到17号染色体q12上的rs7501939（比值比=0.78，95%可信区间=0.72-0.84，P=1.1×10⁻⁹）和19号染色体p12上的rs2195987（比值比=0.76，95%可信区间：0.69-0.84，P=3.2×10⁻⁸）存在全基因组显著关联。17号染色体q12上的标记rs7501939位于HNF1B基因的一个内含子中，该基因编码含同源结构域的转录因子超家族的一个成员。性别决定基因集（错误发现率，FDRM<0.001，FDRI<0.001）以及与核因子κB、甘油磷脂和醚脂代谢以及癌症和凋亡相关的途径与TGCT相关（FDR<0.1）。除了揭示两个新的TGCT易感位点外，我们的结果继续支持子宫内控制正常生殖细胞发育的基因与TGCT发生有关这一观点。
