African American exome sequencing identifies potential risk variants at Alzheimer disease loci.
African American exome sequencing identifies potential risk variants at Alzheimer disease loci.
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DOI：
10.1212/nxg.0000000000000141
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Ertekin-Taner N
中科院分区：
文献类型：
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作者：
N'Songo A;Carrasquillo MM;Wang X;Burgess JD;Nguyen T;Asmann YW;Serie DJ;Younkin SG;Allen M;Pedraza O;Duara R;Greig Custo MT;Graff-Radford NR;Ertekin-Taner N
在非裔美国人中，我们试图系统地识别先前报道的AD全基因组关联研究（GWAS）位点基因的编码阿尔茨海默病（AD）风险变体。我们通过对238名非裔美国人参与者进行全外显子组测序，在20个已发表的AD GWAS位点的基因内确定了编码变异，在另外300名参与者中验证了这些变异，并在538名参与者的联合队列中测试了它们与AD风险的相关性，并在319名参与者中测试了它们与记忆内表型的相关性。两个ABCA7错义变体（rs3764647和rs3752239）与AD风险显著相关。MS4A6A、PTK2B和ZCWPW1的变异体显示出显著的基因相关性。此外，ZCWPW1（rs6465770）和NME8（rs10250905和rs62001869）中的编码变体显示与记忆内表型相关。我们的研究结果支持ABCA7错义变异在非裔美国人中赋予AD风险的作用，突出了该位点的等位基因异质性，表明MS4A6A，PTK2B和ZCWPW1中存在AD风险变异，提名可能调节认知的其他变异，重要的是提供了AD GWAS位点编码变异的全面筛选，可以指导该人群的未来研究。
In African Americans, we sought to systematically identify coding Alzheimer disease (AD) risk variants at the previously reported AD genome-wide association study (GWAS) loci genes. We identified coding variants within genes at the 20 published AD GWAS loci by whole-exome sequencing of 238 African American participants, validated these in 300 additional participants, and tested their association with AD risk in the combined cohort of 538 and with memory endophenotypes in 319 participants. Two ABCA7 missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk. Variants in MS4A6A, PTK2B, and ZCWPW1 showed significant gene-based association. In addition, coding variants in ZCWPW1 (rs6465770) and NME8 (rs10250905 and rs62001869) showed association with memory endophenotypes. Our findings support a role for ABCA7 missense variants in conferring AD risk in African Americans, highlight allelic heterogeneity at this locus, suggest the presence of AD-risk variants in MS4A6A, PTK2B, and ZCWPW1, nominate additional variants that may modulate cognition, and importantly provide a thorough screen of coding variants at AD GWAS loci that can guide future studies in this population.