Whole genome sequence analyses of brain imaging measures in the Framingham Study.
Whole genome sequence analyses of brain imaging measures in the Framingham Study.
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在弗雷明汉研究中，整个基因组序列分析了大脑成像测量。
DOI：
10.1212/wnl.0000000000004820
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发表时间：
2018-01-16
期刊：
影响因子：
9.9
通讯作者：
TOPMed Neurocognitive Working Group
中科院分区：
文献类型：
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作者：
Sarnowski C;Satizabal CL;DeCarli C;Pitsillides AN;Cupples LA;Vasan RS;Wilson JG;Bis JC;Fornage M;Beiser AS;DeStefano AL;Dupuis J;Seshadri S;NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium;TOPMed Neurocognitive Working Group
在弗雷明汉心脏研究中，我们通过进行精确医学反式组学计划的全基因组序列关联分析，试图确定影响脑成像表型的罕见变异。我们对多达2180名个体的大脑和海马体积和白质高强度（WMH）进行了关联分析，通过测试混合效应线性回归模型的等级归一化残差与个体变异的关联，调整了性别、年龄和总颅内容积，同时考虑了家族相关性。我们使用(1)滑动窗口方法，(2)选择功能性外显子变体，或(3)所有变体对罕见变体进行了基于基因的测试。我们在大脑体积1p21（次要等位基因频率[MAF] 0.005, p = 10−8）和海马体积16q23 （MAF 0.05, p = 2.7 × 10−8）检测到新的位点。先前发现的12q24基因与海马体积相关（rs7294919, p = 4.4 × 10−4），17q25基因与WMH相关（rs7214628, p = 2.0 × 10−3）。基于基因的检测检测出大脑（5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13）和海马体积（2p12）以及WMH （3q13, 4p15）新位点的相关性（p≤2.3 × 10−6），包括阿尔茨海默病- (UNC5D)和帕金森病相关基因（GBA）。通路分析证实了免疫、炎症、阿尔茨海默病和帕金森病通路中相关基因的富集。全基因组序列搜索揭示了与大脑测量相关的有趣的新位点。需要对新的基因座进行复制来证实这些发现。
We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program. We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants. We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10−8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10−8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10−4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10−3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10−6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease– (UNC5D) and Parkinson disease–associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways. Whole genome sequence–wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.