Khondoker Mizanur, Newhouse Stephen, Westman Eric, Muehlboeck J-Sebastian, Mecocci Patrizia, Vellas Bruno, Tsolaki Magda, Kłoszewska Iwona, Soininen Hilkka, Lovestone Simon, Dobson Richard, Simmons Andrew
King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Biostatistics, London, United Kingdom.
King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom Departments of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
J Alzheimers Dis. 2015;45(3):851-64. doi: 10.3233/JAD-142214.
Alzheimer's disease (AD) is a highly heritable disease, but until recently few replicated genetic markers have been identified. Markers identified so far are likely to account for only a tiny fraction of the heritability of AD and many more genetic risk alleles are thought to be undiscovered.
Identifying genetic markers for AD using combined analysis of genetics and brain imaging data.
Imaging quantitative trait loci (iQTLs) has recently emerged as an interesting research area for linking genetics of brain changes to AD. We consider a genome-wide association scan of 109 brain-wide regional imaging phenotypes to identify genetic susceptibility loci for AD from a combined set of 1,045 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the AddNeuroMed studies. We use one-SNP-at-a-time as well as multi-SNP Hyperlasso based iQTL methods for the analysis.
We identified several novel markers associated with AD, namely HOMER2 (rs1256429; intronic, p = 8.7 × 10⁻¹⁰), EOMES (rs2724509; flanking), JAM2 (rs2829841; intronic), and WEE1 (rs10770042; coding). The SNP rs1256429 (HOMER2) was one of the top hits in Hyperlasso as well as in the single-SNP analysis showing an association with the volume of the right thalamus and AD, a brain region reported to be linked with AD in several studies.
We believe that the markers identified in this study are novel additions to the existing list of genetic variants associated with AD which can be validated in future replicated studies.
阿尔茨海默病（AD）是一种高度可遗传的疾病，但直到最近才发现少数可重复的遗传标记。目前已发现的标记可能仅占AD遗传度的极小部分，并且人们认为还有更多的遗传风险等位基因尚未被发现。
通过遗传学和脑成像数据的联合分析来识别AD的遗传标记。
成像数量性状基因座（iQTLs）最近已成为将脑变化遗传学与AD联系起来的一个有趣研究领域。我们对109种全脑区域成像表型进行全基因组关联扫描，以从来自阿尔茨海默病神经成像倡议（ADNI）和AddNeuroMed研究的1045名受试者的组合数据集中识别AD的遗传易感性基因座。我们使用一次一个单核苷酸多态性（SNP）以及基于多SNP超套索（Hyperlasso）的iQTL方法进行分析。
我们鉴定出了几个与AD相关的新标记，即HOMER2（rs1256429；内含子，p = 8.7×10⁻¹⁰）、EOMES（rs2724509；侧翼）、JAM2（rs2829841；内含子）和WEE1（rs10770042；编码）。单核苷酸多态性rs1256429（HOMER2）是超套索分析以及单SNP分析中的顶级命中结果之一，显示与右侧丘脑体积和AD相关，在多项研究中均报道该脑区与AD有关联。
我们认为本研究中鉴定出的标记是与AD相关的现有遗传变异列表中的新增内容，可在未来的重复研究中进行验证。
