The impact of non-additive genetic associations on age-related complex diseases.
The impact of non-additive genetic associations on age-related complex diseases.
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DOI：
10.1038/s41467-021-21952-4
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发表时间：
2021-04-23
影响因子：
16.6
通讯作者：
Torrents D
中科院分区：
文献类型：
--
作者：
Guindo-Martínez M;Amela R;Bonàs-Guarch S;Puiggròs M;Salvoro C;Miguel-Escalada I;Carey CE;Cole JB;Rüeger S;Atkinson E;Leong A;Sanchez F;Ramon-Cortes C;Ejarque J;Palmer DS;Kurki M;FinnGen Consortium;Aragam K;Florez JC;Badia RM;Mercader JM;Torrents D
全基因组关联研究并不是完全全面的，因为目前的策略通常只测试相加模型，排除X染色体，并且只使用一个参考小组来进行基因归属。我们实施了一项广泛的GWAS策略，GUIDE，它通过使用多个参考小组来改善基因归因，并包括分析X染色体和非加性模型以测试相关性。我们将这一方法应用于22种年龄相关疾病的62,281名受试者，确定了94个全基因组相关基因座，其中包括26个以前未报道的基因座。此外，我们观察到，如果我们使用具有单一参考面板的标准归因策略，例如HRC，并且只测试加性模型，那么94个座位中有27.7%被遗漏。在新的发现中，我们发现了三个新的低频隐性变异，其优势比大于4，在加性模型下需要至少三倍的大样本才能被检测到。这项研究强调了应用创新策略更好地揭示复杂疾病的遗传结构的好处。大多数全基因组关联研究假设一个加性模型，排除X染色体，并使用一个参考面板。在这里，作者实施了一个包括非加性模型的策略，并发现与单独的加性模型相比，年龄相关性状的基因座数量增加。
Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases. Most genome-wide association studies assume an additive model, exclude the X chromosome, and use one reference panel. Here, the authors implement a strategy including non-additive models and find that the number of loci for age-related traits increases as compared to the additive model alone.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
5.4
作者：
HILL W G;ROBERTSON A
通讯作者：
ROBERTSON A
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
30.8
作者：
Loh, Po-Ru;Danecek, Petr;Palamara, Pier Francesco;Fuchsberger, Christian;Reshef, Yakir A.;Finucane, Hilary K.;Schoenherr, Sebastian;Forer, Lukas;McCarthy, Shane;Abecasis, Goncalo R.;Durbin, Richard;Price, Alkes L.
通讯作者：
Price, Alkes L.