Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Nat Commun. 2022 May 9;13(1):2532. doi: 10.1038/s41467-022-30208-8.
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.
尽管全基因组关联研究取得了成功，但复杂性状的遗传贡献仍有很大一部分尚未得到解释。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偏向稀有谱，且有害变异更常为稀有变异。我们估计，在我们的队列中，罕见变异解释的狭义遗传率不到 4.3%。使用基于基因的方法，我们鉴定了 237 种蛋白质的顺式关联，这略高于全基因组关联研究（N=213），并且我们在 Trans 中鉴定了 34 个相关基因座。几个关联是由罕见变异驱动的，平均而言，这些变异的影响更大。因此，我们得出结论，罕见变异可能对精准医学应用很重要，但对复杂疾病的遗传缺失的贡献有限。
