Lunetta Kathryn L, Erlich Porat M, Cuenco Karen T, Cupples L Adrienne, Green Robert C, Farrer Lindsay A, Decarli Charles
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Alzheimer Dis Assoc Disord. 2007 Apr-Jun;21(2):85-91. doi: 10.1097/WAD.0b013e3180653bf7.
Magnetic resonance imaging (MRI) traits can serve as more specific measures of degenerative or cerebrovascular brain injury than can be ascertained through personal history, risk factors, clinical signs, or symptoms. They are potentially useful intermediate phenotypes for genetic studies of Alzheimer disease (AD). Recent studies have estimated heritability of white matter hyperintensity (WMH) among cognitively normal family members to be between 0.55 and 0.73. Persons discordant for AD are expected to have substantially different MRI phenotype distributions; our goal was to determine whether MRI traits in siblings discordant for AD are heritable. We measured cerebral atrophy, medial temporal atrophy (MTA), WMH, and a rating of cerebrovascular disease (CVR) via MRI in 815 participants from 424 families of the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study. Residual heritability after adjustment for covariates ranged from 0.17 (P=0.009) for MTA to 0.57 (P=10(-7)) for CVR. The number of APOE-epsilon4 alleles was significantly associated with WMH (P=0.01) and CVR (P=0.005) but not cerebral atrophy (P=0.25) or MTA (P=0.83). Heritability remained significant and high after adjusting for APOE genotype, suggesting that a substantial proportion of the additive genetic variation in these MRI traits is explained by other genes. In the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study of AD-discordant siblings, MRI traits are heritable and are potential endophenotypes for genetic association studies.
与通过个人病史、风险因素、临床体征或症状所确定的情况相比，磁共振成像（MRI）特征可作为退行性或脑血管性脑损伤更具特异性的指标。它们是阿尔茨海默病（AD）基因研究中潜在有用的中间表型。最近的研究估计，认知正常的家庭成员中白质高信号（WMH）的遗传度在0.55至0.73之间。预计患AD情况不一致的个体具有明显不同的MRI表型分布；我们的目标是确定患AD情况不一致的兄弟姐妹的MRI特征是否具有遗传性。我们通过MRI测量了来自阿尔茨海默病遗传流行病学多机构研究的424个家庭的815名参与者的脑萎缩、内侧颞叶萎缩（MTA）、WMH以及脑血管疾病评分（CVR）。调整协变量后的残差遗传度范围从MTA的0.17（P = 0.009）到CVR的0.57（P = 10⁻⁷）。APOE-ε4等位基因的数量与WMH（P = 0.01）和CVR（P = 0.005）显著相关，但与脑萎缩（P = 0.25）或MTA（P = 0.83）无关。在调整APOE基因型后，遗传度仍然显著且较高，这表明这些MRI特征中相当一部分加性遗传变异是由其他基因解释的。在阿尔茨海默病遗传流行病学多机构研究中，患AD情况不一致的兄弟姐妹的MRI特征具有遗传性，并且是基因关联研究的潜在内表型。
