Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Nature. 2019 Aug;572(7769):323-328. doi: 10.1038/s41586-019-1457-z. Epub 2019 Jul 31.
Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.
外显子组测序研究通常没有足够的能力来识别对复杂性状有较大影响的有害等位基因，因为这些等位基因大多是罕见的。由于芬兰北部和东部的人口在一系列瓶颈之后大量扩张并孤立，这些人群中的个体拥有大量相对高频的有害等位基因。在这里，我们使用来自这些地区的近 20000 个人的外显子组测序，研究罕见编码变异在临床上相关的定量心脏代谢特征中的作用。对 64 个定量特征的外显子组全基因组关联研究确定了 26 个新的关联有害等位基因。在这 26 个等位基因中，19 个是芬兰个体特有的，或者比其他欧洲人高出 20 多倍，并且表现出与孟德尔疾病突变相当的地理聚类，这些突变是芬兰人群的特征。我们估计，如果没有这种独特历史的人群进行测序研究，需要数十万到数百万参与者才能达到可比的关联能力。
