Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden.
Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Am J Hum Genet. 2018 Jun 7;102(6):1204-1211. doi: 10.1016/j.ajhg.2018.05.002. Epub 2018 May 31.
There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.
对于多种表型中罕见蛋白截断变异的影响，人们的了解有限。我们使用来自 100296 个人的全外显子测序数据，探索了这一类变异对 13 个定量性状和 10 种疾病的影响。在不耐受这类突变的基因中的蛋白截断变异增加了自闭症、精神分裂症、双相情感障碍、智力残疾和 ADHD 的风险。在没有这些疾病的个体中，与身高较矮、教育程度较低、住院次数增加以及入组年龄降低有关。从 GWASs 中确定的基因集没有显示出超出已建立的孟德尔基因所捕获的显著蛋白截断变异负担。总之，我们对罕见有害编码变异对复杂性状的影响进行了全面的研究，表明存在广泛的多效性风险。
