Li Alexander H, Morrison Alanna C, Kovar Christie, Cupples L Adrienne, Brody Jennifer A, Polfus Linda M, Yu Bing, Metcalf Ginger, Muzny Donna, Veeraraghavan Narayanan, Liu Xiaoming, Lumley Thomas, Mosley Thomas H, Gibbs Richard A, Boerwinkle Eric
Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Nat Genet. 2015 Jun;47(6):640-2. doi: 10.1038/ng.3270. Epub 2015 Apr 27.
A typical human exome harbors dozens of loss-of-function (LOF) variants, which can lower disease risk factor levels and affect drug efficacy. We hypothesized that LOF variants are enriched in genes influencing risk factor levels and the onset of common chronic diseases, such as cardiovascular disease and diabetes. To test this hypothesis, we sequenced the exomes of 8,554 individuals and analyzed the effects of predicted LOF variants on 20 chronic disease risk factor phenotypes. Analysis of this sample as discovery and replication strata of equal size verified two relationships in well-studied genes (PCSK9 and APOC3) and identified eight new loci. Previously unknown relationships included elevated fasting glucose in carriers of heterozygous LOF variation in TXNDC5, which encodes a biomarker for type 1 diabetes progression, and apparent recessive effects of C1QTNF8 on serum magnesium levels. These data demonstrate the utility of functional-variant annotation within a large sample of deeply phenotyped individuals for gene discovery.
典型的人类外显子组含有数十个功能丧失（LOF）变异，这些变异可降低疾病风险因素水平并影响药物疗效。我们推测，LOF变异在影响风险因素水平和常见慢性病（如心血管疾病和糖尿病）发病的基因中富集。为了验证这一假设，我们对8554名个体的外显子组进行了测序，并分析了预测的LOF变异对20种慢性病风险因素表型的影响。将该样本作为大小相等的发现和复制层进行分析，验证了两个研究充分的基因（PCSK9和APOC3）中的关系，并确定了八个新位点。以前未知的关系包括，编码1型糖尿病进展生物标志物的TXNDC5基因杂合LOF变异携带者的空腹血糖升高，以及C1QTNF8对血清镁水平的明显隐性影响。这些数据证明了在大量深度表型个体样本中进行功能变异注释对于基因发现的实用性。
