LBPO.PS01 · 人群科学 · Late-Breaking
多人群GWAS荟萃分析鉴定出86个肾细胞癌易感区域
Multi-population GWAS meta-analysis identifies 86 susceptibility regions for renal cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肾细胞癌（RCC）是肾癌的主要类型，其发病率不断上升，尤其是在西方人群中，构成了重大的全球健康挑战。我们对全基因组关联研究（GWAS）进行了多人群荟萃分析，涵盖4个主要大陆人群中的47,838例病例和2,578,530例对照。与既往最大规模的RCC GWAS相比，我们的分析中病例数增加了约60%，非欧洲裔RCC病例数几乎增加了两倍（N = 9,567）。我们鉴定出86个常染色体易感区域，包含122个独立风险位点，其中30个为新发现位点。这包括位于9q24.1区域的rs10217560，其使非洲血统个体的RCC风险升高28%（比值比[OR] = 1.28，95%置信区间[CI]：1.19-1.37），该位点在任何单项研究或其他大陆人群中均未被发现。我们还报告了位于VHL基因5'非翻译区的rs77804868的关联，该位点此前在非洲血统个体中被发现，现在在混合美洲（AMR）个体中同样存在关联，其使RCC风险几乎翻倍（OR AMR = 2.17，95% CI：1.68-2.80）。精细定位在122个位点中鉴定出2,138个候选因果变异，通过肾肿瘤中的cis-eQTL分析将其映射到210个独特基因，其中16个基因基于RCC细胞类型的染色质状态和三维环的activity-by-contact模型获得了进一步证据。下游分析表明，在所鉴定的位点上，RCC肿瘤中的开放染色质区域（p = 1.3E-07）和缺氧诱导因子结合位点（p = 4.6E-08）存在富集。在正常和肿瘤肾组织中进行的全转录组关联研究鉴定出197个与RCC风险相关的基因，其中51%未映射到任何显著的GWAS位点，而全蛋白质组关联研究鉴定出13个显著蛋白，均映射到GWAS位点。我们估计，可归因于所有常见变异的RCC遗传力和家族相对风险分别为18%（CI：14.8%-21.2%）和1.49（CI：1.42-1.56）。在欧洲血统个体中，包含这122个变异的多基因风险评分产生的曲线下面积估计值为0.662（纳入风险因素后为0.752）。综上所述，这些发现大大扩展了我们对RCC遗传结构的认识，为功能研究和风险预测提供了途径。
查看英文原文 English abstract
Renal cell carcinoma (RCC), the predominant form of kidney cancer, represents a significant global health challenge with increasing incidence rates, especially in Western populations. We conducted a multi-population meta-analysis of genome wide association studies including 47,838 cases and 2,578,530 controls across 4 major continental populations. Our analysis reflects an approximate 60% increase in the number of cases with nearly triple the number of non-European RCC cases (N = 9,567) as compared to the previous largest RCC GWAS.We identified 86 autosomal susceptibility regions containing 122 independent risk loci, of which 30 were novel. This included rs10217560 in the 9q24.1 region that increased RCC risk by 28% in African ancestry individuals (odds ratio[OR] = 1.28, 95% confidence interval[CI]: 1.19-1.37) and was not identified in any single study or in other continental populations. We also report the association of rs77804868 in the in the 5′ untranslated region of VHL , previously identified in African ancestry individuals, in admixed American (AMR) individuals as well, which nearly doubles the risk of RCC (OR AMR = 2.17, 95% CI: 1.68-2.80). Fine-mapping identified 2,138 candidate causal variants across the 122 loci which mapped to 210 unique genes through cis-eQTL analysis in kidney tumors of which 16 genes had further evidence from activity-by-contact model based on chromatin state and 3D loops in RCC cell types. Downstream analyses demonstrated an enrichment of accessible chromatin regions in RCC tumors (p = 1.3E-07) and hypoxia-inducible factor-binding sites (p= 4.6E-08) at the identified loci. Transcriptome-wide association studies in normal and tumor kidney tissues identified 197 genes associated with RCC risk of which, 51% did not map to any significant GWAS loci, while proteome-wide association studies identified 13 significant proteins all mapping to GWAS loci. We estimated that the heritability and familial relative risk of RCC attributable to all common variation were 18% (CI: 14.8%-21.2%) and 1.49 (CI:1.42-1.56), respectively. A polygenic risk score including the 122 variants produced an estimated area under the curve of 0.662 (0.752 including risk factors) among European ancestry individuals. Taken together, these findings substantially expand our knowledge of the genetic architecture of RCC providing avenues for functional investigation and risk prediction.
利益披露 Disclosure
D. Dutta, None..
C. Foord, None..
M. J. Machiela, None..
M. P. Purdue, None..
S. J. Chanock, None.