Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN 46202-3082, USA.
Mol Psychiatry. 2013 Jul;18(7):781-7. doi: 10.1038/mp.2013.24. Epub 2013 Apr 23.
Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.
对轻度认知障碍个体进行全外显子组测序，并结合基因分型，利用极端特征设计，鉴定与海马体体积损失率相关的除载脂蛋白 E（APOE）ε4 等位基因以外的编码变异。从阿尔茨海默病神经影像学倡议（ADNI）中选择 APOE ε3 纯合子男性白种人参与者，这些参与者在海马体体积的 2 年纵向变化分布的两端（8 名患者的萎缩速度较快，8 名患者的萎缩速度较慢/稳定）。我们鉴定出 57 个非同义单核苷酸变异（SNV），这些变异仅在快速萎缩组的 8 名患者中的至少 4 名中发现，但在萎缩速度较慢的 8 名患者中均未发现。在这些 SNV 中，在组间差异最大且预测为“可能有害”的错义变异的 SNV 是 rs9610775（CARD10）和 rs1136410（PARP1）。为了在更大的样本中进一步研究和扩展外显子组发现，我们在剩余的 ADNI APOE ε3/ε3 组（N=315）中进行了全脑搜索的定量特征分析。PARP1 和 CARD10 内的遗传变异与 APOE ε3/ε3 患者的海马体神经退行性变速度相关。五项独立横断面队列的荟萃分析表明，rs1136410 也与 APOE ε3/ε3 个体的海马体体积显著相关（N=923）。更大的测序研究和纵向随访仍需要进行以确认。下一代测序和定量成像表型的结合为发现参与神经退行性变的变异提供了很大的希望。
