The Alzheimer's disease GWAS risk alleles in the ABCA7 promoter and 5' region reduce ABCA7 expression.
The Alzheimer's disease GWAS risk alleles in the ABCA7 promoter and 5' region reduce ABCA7 expression.
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DOI：
10.1007/s00401-022-02459-8
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发表时间：
2022-09
影响因子：
12.7
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中科院分区：
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最近刘等人[2]已经提供了来自公开来源的证据，表明阿尔茨海默病 (AD) 相关变体 rs4147929 中三磷酸腺苷结合盒转运蛋白亚家族 A 成员 7 (ABCA7) 位点的风险等位基因与 ABCA7 表达增加相关。我们注意到rs4147929位于基因的3’端，那里几乎没有顺式作用调控元件，并且与rs3752246处于完美的连锁不平衡(LD)（两者的风险等位基因频率[RAF]=0.19，R2=0.97），这是一种可能影响ABCA7翻译后修饰的错义变体（Val1527Gly）[1]。 ABCA7 的启动子和 5' 端还包含基因组显着的 AD 相关变异，这些变异尚未被 Liu 等人检查过（补充图 1 和 2，在线资源）。我们研究了 16 个 AD 相关变异，这些变异在最近的 AD GWAS 中具有最低的 p 值，并且分布在整个 ABCA7 位点上，与脑组织中的 ABCA7 表达相关（补充表 1 和 2，在线资源）。检查 GTEx (n= 165–205)、ROSMAP (n= 534)、Mayo RNAseq (n≈ 260)、CommonMind (n= 598)、PsychENCODE (n= 1866)、BrainSeq（第 1 阶段 n= 412、第 2 阶段 n= 551）、Lopes 等人（仅小胶质细胞，n= 100) 和 ROSMAP/Mayo RNAseq/CommonMind (n= 1433) 和 ROSMAP/GTEx v. 8/PsychENCODE (n= 2119) 荟萃分析显示，其中 15 个变异与某些脑组织中的 ABCA7 表达相关，处于标称或调整后的显着性水平，并整齐地分为两个不重叠的组（图 1a；补充说明，补充参考文献，补充表 3-11，在线资源）。第一组变体中的风险等位基因与较低的ABCA7表达相关或与ABCA7转录物水平无关，而第二组中的变体中的风险等位基因与较高的ABCA7表达相关或与ABCA7转录物水平无关。例如，rs111278892处的风险等位基因（第一组中的变异体）与海马体（GTEx p= 3.4×10-3，p阈值[p th]= 1.1×10-5）和大脑皮层（ROSMAP p= 0.04，p th= 8× 10-8；Mayo RNAseq p= 0.03）中ABCA7表达减少相关，错误发现率 [FDR]= 0.6，FDR= 0.005；ROSMAP/Mayo RNAseq/CommonMind p= 7.2× 10–6，FDR= 4.3× 10–4；ROSMAP/GTEx v. 8/PsychENCODE 8.0× 10–7，p th= 1× 10-6）但不在小脑中（GTEx p= 0.6-0.15；Mayo RNAseq p= 0.17）。属于第二组的编码变体 rs3752246 的风险等位基因与小脑中 ABCA7 表达增加相关 (GTEx p= 1.7× 10− 7− 2.9× 10–12, p th= 2.8× 10− 5− 3.1× 10–5; Mayo RNAseq p= 1.9× 10–6, FDR= 4.7× 10–4）和大脑皮层（ROSMAP/Mayo RNAseq/CommonMind p= 3.7× 10–6，FDR= 2.3× 10–4；ROSMAP/GTEx v. 8/PsychENCODE p= 1.7× 10–17，p th= 1× 10–6），但不在海马体中（GTEx p= 0.09）。第二组包括另一个错义变体 rs3764645 (Glu188Gly)。 ABCA1 是与 ABCA7 密切相关的转运蛋白，其突变位于 ABCA7 中 rs3764645 和 rs3752246 位置对应的区域，会损害 ABCA1 活性 [4]。第一组中的变体倾向于位于ABCA7的启动子或5’区域，而第二组中的变体倾向于位于该基因的3’区域。当 15 个变体中的任何一个出现 LD 时，风险等位基因总是相关的（补充表 12 和 13，在线资源）。 rs72973584 (RAF= 0.11) 和 rs3752246 (RAF= 0.19) 处的风险等位基因处于紧密状态。
Recently Liu et al.[2] have presented evidence from publicly available sources that the risk allele in the Alzheimer’s disease (AD)-associated variant rs4147929 at the adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) locus is associated with increased ABCA7 expression. We noticed that rs4147929 is located at the 3’end of the gene where there are few cis-acting regulatory elements and is in a perfect linkage disequilibrium (LD) with rs3752246 (risk allele frequency [RAF]= 0.19 for both, R2= 0.97), a missense variant (Val1527Gly) that may affect ABCA7 post-translational modification [1]. The promoter and 5’end of ABCA7 also contain genome-significant AD-associated variants that have not been inspected by Liu et al.(Supplementary Fig. 1 and 2, online resource). We investigated 16 AD-associated variants that had the lowest p values in the recent AD GWAS and were distributed along the entire ABCA7 locus for the association with ABCA7 expression in brain tissues (Supplementary Table 1 and 2, online resource). An inspection of the summary statistics from GTEx (n= 165–205), ROSMAP (n= 534), Mayo RNAseq (n≈ 260), CommonMind (n= 598), PsychENCODE (n= 1866), BrainSeq (phase 1 n= 412, phase 2 n= 551), Lopes et al.(microglia only, n= 100) and the ROSMAP/Mayo RNAseq/CommonMind (n= 1433) and ROSMAP/GTEx v. 8/PsychENCODE (n= 2119) meta-analyses revealed that 15 of the variants were associated with ABCA7 expression in certain brain tissues at a nominal or adjusted level of significance and neatly segregated into two nonoverlapping groups (Fig. 1 a; Supplementary Notes, Supplementary References, Supplementary Table 3–11, online resource). The risk alleles in the variants comprising the first group were correlated with lower ABCA7 expression or had no association with ABCA7 transcript levels, while the risk alleles in the variants in the second group were associated with higher ABCA7 expression or had no association with ABCA7 transcript levels. For example, the risk allele at rs111278892, a variant in the first group, was associated with reduced ABCA7 expression in the hippocampus (GTEx p= 3.4× 10–3, p threshold [p th]= 1.1× 10–5) and cerebral cortex (ROSMAP p= 0.04, p th= 8× 10–8; Mayo RNAseq p= 0.03, false discovery rate [FDR]= 0.6; CommonMind p= 6.9× 10− 5, FDR= 0.005; ROSMAP/Mayo RNAseq/CommonMind p= 7.2× 10–6, FDR= 4.3× 10–4; ROSMAP/GTEx v. 8/PsychENCODE 8.0× 10–7, p th= 1× 10–6) but not in the cerebellum (GTEx p= 0.6–0.15; Mayo RNAseq p= 0.17). The risk allele at the coding variant rs3752246, which fell into the second group, was associated with increased ABCA7 expression in the cerebellum (GTEx p= 1.7× 10− 7− 2.9× 10–12, p th= 2.8× 10− 5− 3.1× 10–5; Mayo RNAseq p= 1.9× 10–6, FDR= 4.7× 10–4) and cerebral cortex (ROSMAP/Mayo RNAseq/CommonMind p= 3.7× 10–6, FDR= 2.3× 10–4; ROSMAP/GTEx v. 8/PsychENCODE p= 1.7× 10–17, p th= 1× 10–6) but not in the hippocampus (GTEx p= 0.09). The second group included another missense variant rs3764645 (Glu188Gly). Mutations in ABCA1, a transporter closely related to ABCA7, in the regions corresponding to the locations of rs3764645 and rs3752246 in ABCA7 impair ABCA1 activity [4]. The variants in the first group tended to reside in the promoter or 5’region of ABCA7, while those in the second group tended to locate at the 3’area of the gene. When any of the 15 variants were in LD, the risk alleles were always correlated (Supplementary Table 12 and 13, online resource). The risk alleles at rs72973584 (RAF= 0.11) and rs3752246 (RAF= 0.19) were in a tight