An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition.
An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition.
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DOI：
10.1016/j.neurobiolaging.2022.05.011
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发表时间：
2022-10
影响因子：
4.2
通讯作者：
Walsh, Kyle M.
中科院分区：
文献类型：
--
作者：
Khaire, Archita S.;Wimberly, Courtney E.;Semmes, Eleanor C.;Hurst, Jillian H.;Walsh, Kyle M.
全基因组关联研究（GWAS）已经确定了增加晚发性阿尔茨海默病（LOAD）风险的常见单核苷酸多态性（SNP）。为了鉴定其他与LOAD相关的变异并提供对潜在疾病生物学的深入了解，我们使用英国生物库数据对23个已知的与LOAD相关的SNP和4：1匹配的对照SNP进行了全表型关联研究（PheWAS）。负载相关的SNPs显着富集与8/778查询性状，包括三个血小板性状的关联。最强的富集是血小板分布宽度（PDW）（P=1.2×10−5），但在孟德尔随机化分析中，PDW增加与LOAD易感性无关。在先前GWAS鉴定的384个PDW相关SNP中，36个名义上与LOAD风险相关（17，008例; 37，154例对照），5个在错误发现率校正后存活。相关性证实了PICALM、CD 2AP、SPI 1和NDUFAF 6附近已知的LOAD风险位点，并在EGFR中发现了一个新的风险位点。整合GWAS和PheWAS数据揭示了LOAD和血小板形态的遗传决定因素之间的大量多效性，并首次暗示EGFR -β-淀粉样蛋白毒性的介导物-在阿尔茨海默病易感性中。
Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs) that increase late-onset Alzheimer’s disease (LOAD) risk. To identify additional LOAD-associated variants and provide insight into underlying disease biology, we performed a phenome-wide association study (PheWAS) on 23 known LOAD-associated SNPs and 4:1 matched control SNPs using UK Biobank data. LOAD-associated SNPs were significantly enriched for associations with 8/778 queried traits, including three platelet traits. The strongest enrichment was for platelet distribution width (PDW) (P=1.2×10−5), but increased PDW was not associated with LOAD susceptibility in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk (17,008 cases; 37,154 controls) and 5 survived false-discovery rate correction. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in EGFR. Integrating GWAS and PheWAS data reveals substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicates EGFR – a mediator of β-amyloid toxicity – in Alzheimer’s disease susceptibility.
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影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
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DOI：
10.1146/annurev-genom-090314-024956
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影响因子：
4.8
作者：
Jian C;Wei L;Mo R;Li R;Liang L;Chen L;Zou C;Meng Y;Liu Y;Zou D
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