Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions.
Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions.
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DOI：
10.3233/jad-2011-101932
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Younkin SG
中科院分区：
文献类型：
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作者：
Carrasquillo MM;Belbin O;Hunter TA;Ma L;Bisceglio GD;Zou F;Crook JE;Pankratz VS;Sando SB;Aasly JO;Barcikowska M;Wszolek ZK;Dickson DW;Graff-Radford NR;Petersen RC;Morgan K;Younkin SG
最近的晚发性阿尔茨海默病（LOAD）全基因组关联研究显示，两个新位点的全基因组显著关联：BIN 1附近的rs744373（p=1.6×10−11）和EXOC 3L 2/BLOC 1 S3/MARK 4附近的rs 597668（p=6.5×10−9）。我们在一个大型（3，287 LOAD，4，396对照）独立数据集中对这些变异进行了基因分型，该数据集包括来自美国和欧洲的11个病例对照系列。我们对这些变异与LOAD的关联进行了荟萃分析，并使用logistic回归进行了相关性检验，该回归通过诊断时的年龄、性别和APOE ε4状态进行了调整。荟萃分析结果显示，没有证据表明存在系列异质性，logistic回归分析成功复制了BIN 1（rs744373）与LOAD的相关性，比值比（OR=1.17，p=1.1×10−4）与先前报告的比值比（OR=1.15）相当。在校正APOE ε4等位基因的存在后，EXOC 3L 2附近的变体（rs 597668）仅显示与LOAD的暗示性关联（p=0.09）。将我们的随访数据添加到先前报告的结果中，增加了与BIN 1相关的证据强度（11，825 LOAD，32，570对照，rs744373 Fisher组合p=3.8×10−20）。我们还检测了这些变体与APOEε4以及先前复制的LOAD GWAS基因（CLU：rs 11136000、CR 1; rs3818361和PICALM：rs3851179）之间的上位相互作用。这些基因之间没有显著的相互作用。总之，我们为BIN 1附近的变异（rs744373）作为LOAD风险调节因子提供了额外的证据，但我们的结果表明，EXOC 3L 2独立于APOE ε4的影响应进一步研究。
The most recent late-onset Alzheimer’s disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p=6.5×10−9). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, sex and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR=1.17, p=1.1×10−4) comparable to that previously reported (OR=1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p=0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p=3.8×10−20). We also tested for epistatic interaction between these variants and APOEε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1; rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further.