Abstract：
Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported.
Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).
We identified 6 genome-wide significant (P < 5 × 10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10-19) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.
Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.
Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls).
We identified 6 genome-wide significant (P < 5 × 10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10-19) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.
Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.
摘要：
目的：小肠神经内分泌肿瘤（SI-NET）是一种罕见的疾病，其发病率在过去的40年中有所增加。了解SI-NET潜在的遗传风险因素有助于疾病预防，并可能为诊断提供临床有益的标志物。这里,我们报告了迄今为止对SI-NETs进行的最大规模的全基因组关联研究(GWAS)的结果,该研究涉及405例病例和614,666例对照.
方法：我们在FinnGen研究中使用了307名SI-NET患者和287,137名对照的样本来鉴定SI-NET风险相关的遗传变异。我们还使用UKBiobank的汇总统计数据（n=98SI-NET病例，n=327,529个对照）对结果进行了分析。
结果：我们确定了6个与SI-NET风险相关的全基因组显著（p<5x10-8）基因座，其中4个(靠近SEMA6A，LGR5，CDKAL1和FERMT2）是新颖的，并且2（在LTA4H-ELK附近和KIF16B中）已被报道。有趣的是,最高命中（rs200138614，p=1.80x10-19）是一个错误的变体（p。Cys712Phe）在LGR5基因中，成人肠道干细胞的真正标记和经典WNT信号的增效剂。该关联在芬兰独立收集的70名SI-NET患者中得到验证，以及英国生物样本库外显子组序列数据(n=92例，n=392,814例对照)。肠类器官中LGR5p.Cys712Phe的过表达消除了R-Spondin1支持类器官生长的能力，表明突变扰乱了R-Spondin-LGR5信号传导。
结论：我们的研究是迄今为止针对SI-NET的最大的GWAS研究，并报告了4个新的相关GWAS基因座，包括LGR5中的一个新的错义突变（rs200138614，p.Cys712Phe），LGR5是成人肠干细胞的规范标记。
方法：我们在FinnGen研究中使用了307名SI-NET患者和287,137名对照的样本来鉴定SI-NET风险相关的遗传变异。我们还使用UKBiobank的汇总统计数据（n=98SI-NET病例，n=327,529个对照）对结果进行了分析。
结果：我们确定了6个与SI-NET风险相关的全基因组显著（p<5x10-8）基因座，其中4个(靠近SEMA6A，LGR5，CDKAL1和FERMT2）是新颖的，并且2（在LTA4H-ELK附近和KIF16B中）已被报道。有趣的是,最高命中（rs200138614，p=1.80x10-19）是一个错误的变体（p。Cys712Phe）在LGR5基因中，成人肠道干细胞的真正标记和经典WNT信号的增效剂。该关联在芬兰独立收集的70名SI-NET患者中得到验证，以及英国生物样本库外显子组序列数据(n=92例，n=392,814例对照)。肠类器官中LGR5p.Cys712Phe的过表达消除了R-Spondin1支持类器官生长的能力，表明突变扰乱了R-Spondin-LGR5信号传导。
结论：我们的研究是迄今为止针对SI-NET的最大的GWAS研究，并报告了4个新的相关GWAS基因座，包括LGR5中的一个新的错义突变（rs200138614，p.Cys712Phe），LGR5是成人肠干细胞的规范标记。
