PO.PS01.03 · 人群科学
美国欧洲血统和混合非洲血统人群中的等位基因频率差异不能完全解释成人型弥漫性胶质瘤的发病率差异
Allele frequency variation in people of European and admixed African ancestry in the United States do not fully explain incidence differences in adult-type diffuse glioma
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摘要 Abstract
中文摘要
背景 胶质瘤是一组异质性肿瘤，构成了最常见的原发性恶性脑肿瘤类型。其发病率在全球范围内各不相同，欧洲和北美最高，亚洲和非洲最低。在美国境内，这些肿瘤在非西班牙裔白人个体中最常见。此前，全基因组关联研究（GWAS）已识别出25个影响胶质瘤风险的单核苷酸多态性（SNP）（仅限欧洲人群），其中大多数具有亚型特异性差异。SNP等位基因频率（AF）在各大洲人群之间存在差异。我们估算了成人型弥漫性胶质瘤各亚型的人群水平发病率，并计算了观察到的差异与可归因于AF差异的差异之间的差别。
方法 使用美国中央脑肿瘤登记处（CDC国家癌症登记项目与NCI SEER的汇总数据），计算了2018-2022年诊断年份胶质瘤各亚型（IDH1/2突变型星形细胞瘤[IDHmut]、IDH1/2野生型星形细胞瘤[IDHwt]，以及伴IDH1/2突变和1p/19q共缺失的少突胶质细胞瘤[IDHmut-codel]）按种族/族裔分层的年龄标化发病率。以非西班牙裔白人为对照估算发病率比（IRR O）。已知胶质瘤风险SNP的效应估计值取自此前一项亚型特异性胶质瘤GWAS（Labreche，2018），选取p<4x10-4的SNP。AF取自等位基因频率聚合器（Allele Frequency Aggregator）中的欧洲人群和非裔美国人群数据。我们基于人群AF计算每个SNP的标准化IRR（IRR N），并将其求和以估算可归因于AF的发病率差异。IRR N通过将beta值乘以相应的AF计算得出。
结果 与非西班牙裔白人个体相比，非西班牙裔黑人个体所有亚型的发病率均降低[IDHmut IRR O=0.40，IDHwt IRR O=0.49，IDHmut-codel IRR O=0.29]。与观察到的发病率相比，IRR N有所减弱[IDH-mut IRR N=0.78，IDH-wt IRR N=0.75，IDHmut-codel IRR N=0.64]。IRR N高于IRR O，其中最大的差异出现在非西班牙裔黑人人群中。
结论 IRR N未能完全解释胶质瘤发病率的人群差异。这可能是由于GWAS中祖先多样性有限所致，这些研究尚未在非裔美国人个体中评估SNP。亚型特异性GWAS的样本量一直较小且检验效能不足。这些SNP并未涵盖胶质瘤的全部遗传风险（所有已识别的SNP仅解释了30%的可遗传风险），存在显著的'遗传力缺失'。这些结果强调了在胶质瘤遗传流行病学研究中纳入更多样化人群的必要性，以确保遗传风险估计的准确性。
查看英文原文 English abstract
Background Glioma is a heterogeneous group of tumors that make up the most common type of primary malignant brain tumor. Incidence varies globally, with highest rates in Europe and North America and lowest in Asia and Africa. Within the United States, these tumors are most common in individuals who are non-Hispanic White. Previously, genome-wide association studies (GWAS) have identified 25 single nucleotide polymorphisms (SNPs) which affect risk for glioma (European only), most of which have subtype-specific differences. SNP allele frequencies (AF) vary between continental populations. We estimated population-level incidence for adult-type diffuse glioma subtypes and calculated the difference between observed variation and variation attributable to AF differences.
Methods Race/ethnicity-stratified age-adjusted incidence rates for glioma subtypes (Astrocytoma with IDH1/2 mutation [IDHmut], Astrocytoma with wildtype IDH1/2 [IDHwt], and Oligodendroglioma with IDH1/2 mutation and 1p/19q codeletion [IDHmut-codel]) from diagnosis years 2018-2022 were calculated using the Central Brain Tumor Registry of the United States, an aggregation of CDC's National Program of Cancer Registries and NCI's SEER. Incidence rate ratios (IRR O ) were estimated as compared to non-Hispanic White. Effect estimates for known glioma risk SNPs were extracted from a prior subtype-specific glioma GWAS (Labreche, 2018) for SNPs with p<4x10 -4 . AF were extracted from the Allele Frequency Aggregator for the European and African American populations. We calculated the normalized IRR (IRR N ) for each SNP based on population AF and summed these to estimate the incidence variation attributable to AF. IRR N was calculated by multiplying the beta by the corresponding AF.
Results As compared to individuals who are non-Hispanic White, incidence was decreased in non-Hispanic Black individuals for all subtypes [IDHmut IRR O =0.40, IDHwt IRR O =0.49, IDHmut-codel IRR O =0.29]. IRR N were attenuated as compared to observed rates [IDH-mut IRR N =0.78, IDH-wt IRR N =0.75, IDHmut-codel IRR N =0.64]. The IRR N is higher compared to the IRR O , with the greatest differences being observed in the non-Hispanic Black population.
Conclusion IRR N fail to fully explain population differences in incidence of glioma. This may be a result of limited ancestral diversity in GWAS, which have not assessed SNPs in individuals who are African American. Sample sizes for subtype-specific GWAS have been small and underpowered. These SNPs do not capture all genetic risk for glioma (all identified SNPs explain 30% of heritable risk), and there is significant ‘missing heritability.' These results emphasize the need for inclusion of more diverse populations in glioma genetic epidemiology to ensure accurate genetic risk estimation.
利益披露 Disclosure
C. A. Ballard, None..
C. Kruchko, None..
M. Price, None.