Abstract

Variants in APOE are associated with risk of late onset Alzheimer's disease (LOAD) but the magnitude of the effect has been reported to vary across ancestries. Also, other variants in the region have been reported to show association though it has been unclear whether this was secondary to their linkage disequilibrium with the APOE variants rs429358 and rs7412. Previous analyses of exome-sequenced samples have identified other genes in which rare variants impact risk of disease. In this study 2000 whole genome sequenced cases and controls with different ancestries were subjected to gene-based weighted burden analysis to identify risk genes. Additionally, individual variants in the APOE region were tested for association with LOAD. When using the APOE variants as covariates no individual genes showed statistically significant evidence for association after Bonferroni correction for multiple testing, which may well be a consequence of the modest sample size. Likewise, for those variants initially showing evidence of association with LOAD incorporating the APOE variants as covariates dramatically reduced the strength of association. These results demonstrate that the differential association of APOE across ancestries does not appear to be driven by another variant in the region. It seems likely that no other genes in the region have a direct effect on LOAD risk.

摘要

APOE 的变异与迟发性阿尔茨海默病 (LOAD) 的风险相关，但据报道影响的大小因血统而异。此外，据报道，该地区的其他变体显示出关联，尽管尚不清楚这是否继发于它们与APOE变体 rs429358 和 rs7412的连锁不平衡。先前对外显子组测序样本的分析已经确定了其他基因，其中罕见变异会影响疾病风险。在这项研究中，对 2000 个全基因组测序病例和具有不同血统的对照进行了基于基因的加权负担分析，以识别风险基因。此外，还测试了APOE区域中的单个变体与 LOAD 的关联。使用时APOE变体作为协变量，在针对多重测试的 Bonferroni 校正后，没有单个基因显示出具有统计学意义的关联证据，这很可能是样本量适中的结果。同样，对于那些最初显示与 LOAD 关联证据的变体，将APOE变体作为协变量显着降低了关联强度。这些结果表明，APOE跨血统的差异关联似乎不是由该地区的另一个变体驱动的。该地区似乎没有其他基因对负载风险有直接影响。