On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration
On the differences between mega‐ and meta‐imputation and analysis exemplified on the genetics of age‐related macular degeneration
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论megaâ和metaâcomputation之间的差异以及以年龄相关性黄斑变性的遗传学为例的分析
DOI：
10.1002/gepi.22204
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发表时间：
2019
影响因子：
2.1
通讯作者：
Heid IM
中科院分区：
文献类型：
--
作者：
Gorski M;Guenther F;Winkler TW;Weber BHF;Heid IM
虽然当前的全基因组关联分析通常依赖于研究特定汇总统计数据的荟萃分析，但来自多项研究的个体参与者数据 (IPD) 增加了建模的选择。然而，当多研究 IPD 可用时，尚不清楚这些数据是对所有参与者进行估算和建模（大规模估算和大规模分析）还是针对特定研究（荟萃估算和荟萃分析）。在这里，我们使用来自国际年龄相关性黄斑变性 (AMD) 基因组联盟 25 项研究的 52,189 名受试者，包括 16,144 个 AMD 病例和 17,832 个对照进行关联分析，研究了不同的插补和分析方法。在基于 1,000 个基因组的插补后，从 27,448,454 个遗传变异中，大型插补产生了约 400,000 个以上的变异与元插补相比，插补质量较高（主要是罕见的变体）。对于大型插补数据中的AMD信号检测（P< 5 × 10−8），大多数基因座是通过大型分析检测到的，无需调整研究成员资格（40个基因座，包括34个已知基因座）；我们认为这些位点是真实的，因为遗传效应和 P 值在分析中具有可比性。在元插补数据中，我们发现了 31 个额外信号，大部分靠近染色体尾部或参考组间隙，在考虑全基因组扩增 (WGA) 与研究成员资格的相互作用或排除 WGA 参与者的研究后，这些信号消失了。对于多研究 IPD 的信号检测，我们建议采用大型插补和大型分析，其中元插补后进行荟萃分析是一种计算上有吸引力的替代方案。
While current genome‐wide association analyses often rely on meta‐analysis of study‐specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and modeled across all participants (mega‐imputation and mega‐analysis) or study‐specifically (meta‐imputation and meta‐analysis). Here, we investigated different approaches toward imputation and analysis using 52,189 subjects from 25 studies of the International Age‐related Macular Degeneration (AMD) Genomics Consortium including, 16,144 AMD cases and 17,832 controls for association analysis.From 27,448,454 genetic variants after 1,000‐Genomes‐based imputation, mega‐imputation yielded ~400,000 more variants with high imputation quality (mostly rare variants) compared to meta‐imputation. For AMD signal detection (P< 5 × 10−8) in mega‐imputed data, most loci were detected with mega‐analysis without adjusting for study membership (40 loci, including 34 known); we considered these loci genuine, since genetic effects andP‐values were comparable across analyses. In meta‐imputed data, we found 31 additional signals, mostly near chromosome tails or reference panel gaps, which disappeared after accounting for interaction of whole‐genome amplification (WGA) with study membership or after excluding studies with WGA‐participants.For signal detection with multistudy IPD, we recommend mega‐imputation and mega‐analysis, with meta‐imputation followed by meta‐analysis being a computationally appealing alternative.
影响因子：
2.7
作者：
Lin, D. Y.;Zeng, D.
通讯作者：
Zeng, D.
影响因子：
1.9
作者：
Olkin, I;Sampson, A
通讯作者：
Sampson, A