Discovery of common and rare genetic risk variants for colorectal cancer
Discovery of common and rare genetic risk variants for colorectal cancer
复制标题
DOI：
10.1038/s41588-018-0286-6
复制
发表时间：
2019-01-01
期刊：
影响因子：
30.8
通讯作者：
Peters, Ulrike
中科院分区：
文献类型：
--
作者：
Huyghe, Jeroen R.;Bien, Stephanie A.;Peters, Ulrike
为了进一步剖析结直肠癌（CRC）的遗传结构，我们对1，439例病例和720例对照进行了全基因组测序，将发现的序列变异和单倍型参考联盟面板变异纳入全基因组关联研究数据，并在34，869例病例和29，051例对照中进行了关联性测试。在另外23，262例病例和38，296例对照中对结果进行了随访。我们在CHD 1处发现了强保护性的0.3%频率变化信号。在对125，478名个体进行的综合荟萃分析中，我们在P < 5 x 10（-8）时发现了40个新的独立信号，使CRC的已知独立信号数量接近100。新的信号涉及低频变异，Kruppel样因子，Hedgehog信号传导，Hippo-YAP信号传导，长非编码RNA和体细胞驱动因子，并支持免疫功能的作用。遗传性分析表明，CRC风险是高度多基因的，更大，更全面的研究，使罕见变异分析将提高对这种风险的生物学基础的理解，并影响个性化的筛选策略和药物开发。
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.