Lyall Donald M, Harris Sarah E, Bastin Mark E, Muñoz Maniega Susana, Murray Catherine, Lutz Michael W, Saunders Ann M, Roses Allen D, Valdés Hernández Maria del C, Royle Natalie A, Starr John M, Porteous David J, Wardlaw Joanna M, Deary Ian J
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, UK; Department of Psychology, University of Edinburgh, Edinburgh, UK; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine, Western General Hospital, Edinburgh, UK; MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine, Western General Hospital, Edinburgh, UK; MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
Neurobiol Aging. 2014 Jun;35(6):1513.e25-33. doi: 10.1016/j.neurobiolaging.2014.01.006. Epub 2014 Jan 8.
Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 ("523") variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640-650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 "risk" allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 "short" allele showed lower white matter integrity when compared with carriers of the "long" and "very-long" alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.
载脂蛋白E（APOE）ε基因型先前已与认知、脑成像及阿尔茨海默病相关表型（如发病年龄）显著相关。在TOMM40基因中，rs10524523（“523”）可变长度多聚T重复多态性最近也与类似表型相关，尽管这些关联的等位基因方向在最初报告之间有所不同。本研究使用扩散磁共振成像纤维束成像技术，旨在调查在一个社区居住的老年人样本——洛锡安1936年出生队列（平均年龄 = 72.70岁，标准差 = 0.74，大多数分析中N约为640 - 650）中，载脂蛋白E（APOE）和TOMM40基因型对人脑白质完整性是否有独立影响。观察到了一些名义上显著的效应（即基因型组之间经协变量调整后的差异，p < 0.05）。对于APOE，发现ε4“风险”等位基因存在（与不存在相比）在右侧腹侧扣带和左侧下纵束中有有害影响。为了测试TOMM40 523重复的生物学独立效应，将参与者分层为APOE基因型亚组，以便任何显著效应不能归因于APOE变异。在APOE ε3/ε基因型的参与者中，发现TOMM40 523状态在左侧钩束、左侧喙侧扣带、左侧腹侧扣带以及白质完整性的一个一般因素中有效应。在所有这4种纤维束成像测量中，与“长”和“非常长”等位基因携带者相比，TOMM40 523“短”等位基因携带者的白质完整性较低。这些效应中的大多数在对儿童智力测试分数和血管疾病史进行校正后仍然存在，不过只有TOMM40 523对左侧腹侧扣带完整性的效应在对错误发现率进行校正后仍然存在。与先前研究报告的效应相比，APOE在这个老年人群中的效应更具特异性且更受限制，并且TOMM40对白质完整性的效应似乎是新发现的，尽管需要在大型独立样本中进行重复验证。
