Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability.
Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability.
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DOI：
10.1038/s41467-022-30208-8
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发表时间：
2022-05-09
影响因子：
16.6
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中科院分区：
文献类型：
--
作者：
尽管全基因组关联研究取得了成功，但许多复杂性状的遗传贡献仍未得到解释。在这里，我们分析了高覆盖率的全基因组测序数据，以评估罕见遗传变异对414种血浆蛋白的贡献。遗传变异的频率分布倾向于罕见谱，而破坏性变异往往更为罕见。我们估计，在我们的队列中，只有不到4.3%的狭义遗传力可以用罕见变异来解释。使用基于基因的方法，我们鉴定了237个蛋白质的顺式关联，这比GWAS （N = 213）稍多，我们鉴定了34个Trans相关位点。一些关联是由罕见的变异驱动的，这些变异的平均影响更大。因此，我们得出结论，罕见变异可能对精准医学应用很重要，但对复杂疾病的缺失遗传性的贡献更有限。尽管全基因组关联研究取得了成功，但许多复杂性状的遗传贡献仍未得到解释。在这里，作者确定了罕见变异对血浆蛋白的影响，并估计了罕见变异对遗传性的贡献。
Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, we analyse high coverage whole-genome sequencing data, to evaluate the contribution of rare genetic variants to 414 plasma proteins. The frequency distribution of genetic variants is skewed towards the rare spectrum, and damaging variants are more often rare. We estimate that less than 4.3% of the narrow-sense heritability is expected to be explained by rare variants in our cohort. Using a gene-based approach, we identify Cis-associations for 237 of the proteins, which is slightly more compared to a GWAS (N = 213), and we identify 34 associated loci in Trans. Several associations are driven by rare variants, which have larger effects, on average. We therefore conclude that rare variants could be of importance for precision medicine applications, but have a more limited contribution to the missing heritability of complex diseases. Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, the authors identify effects by rare variants on plasma proteins, and estimate the contribution of rare variants to the heritability.
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影响因子：
56.9
作者：
Akbari, Parsa;Gilani, Ankit;Sosina, Olukayode;Kosmicki, Jack A.;Khrimian, Lori;Fang, Yi-Ya;Persaud, Trikaldarshi;Garcia, Victor;Sun, Dylan;Li, Alexander;Mbatchou, Joelle;Locke, Adam E.;Benner, Christian;Verweij, Niek;Lin, Nan;Hossain, Sakib;Agostinucci, Kevin;Pascale, Jonathan, V;Dirice, Ercument;Dunn, Michael;Kraus, William E.;Shah, Svati H.;Chen, Yii-Der, I;Rotter, Jerome, I;Rader, Daniel J.;Melander, Olle;Still, Christopher D.;Mirshahi, Tooraj;Carey, David J.;Berumen-Campos, Jaime;Kuri-Morales, Pablo;Alegre-Diaz, Jesus;Torres, Jason M.;Emberson, Jonathan R.;Collins, Rory;Balasubramanian, Suganthi;Hawes, Alicia;Jones, Marcus;Zambrowicz, Brian;Murphy, Andrew J.;Paulding, Charles;Coppola, Giovanni;Overton, John D.;Reid, Jeffrey G.;Shuldiner, Alan R.;Cantor, Michael;Kang, Hyun M.;Abecasis, Goncalo R.;Karalis, Katia;Economides, Aris N.;Marchini, Jonathan;Yancopoulos, George D.;Sleeman, Mark W.;Altarejos, Judith;Della Gatta, Giusy;Tapia-Conyer, Roberto;Schwartzman, Michal L.;Baras, Aris;Ferreira, Manuel A. R.;Lotta, Luca A.
通讯作者：
Lotta, Luca A.
影响因子：
16.6
作者：
Hillary, Robert F.;McCartney, Daniel L.;Marioni, Riccardo E.
通讯作者：
Marioni, Riccardo E.
影响因子：
4.6
作者：
Enroth, Stefan;Maturi, Varun;Gyllensten, Ulf
通讯作者：
Gyllensten, Ulf
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
16.6
作者：
Cirulli, Elizabeth T.;White, Simon;Washington, Nicole L.
通讯作者：
Washington, Nicole L.