Silva Claudia Tamar, Zorkoltseva Irina V, Niemeijer Maartje N, van den Berg Marten E, Amin Najaf, Demirkan Ayşe, van Leeuwen Elisa, Iglesias Adriana I, Piñeros-Hernández Laura B, Restrepo Carlos M, Kors Jan A, Kirichenko Anatoly V, Willemsen Rob, Oostra Ben A, Stricker Bruno H, Uitterlinden André G, Axenovich Tatiana I, van Duijn Cornelia M, Isaacs Aaron
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), GENIUROS Research group, School of Medicine and Health Science, Universidad del Rosario, Bogotá, Colombia.
BMC Med Genomics. 2018 Mar 5;11(1):22. doi: 10.1186/s12920-018-0339-9.
Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them.
The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data.
We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied.
We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.
左心室肥厚(LVH)的心电图测量指标被用作心血管风险的预测指标。我们结合连锁分析和关联分析来发现与三种此类测量指标以及由它们衍生的两个主成分相关的新型罕见遗传变异。
该研究在伊拉斯姆斯鲁芬家族研究(ERF)的参与者中进行,ERF是来自荷兰西南部的一个基于家族的样本。使用Merlin进行方差成分连锁分析。使用微阵列和外显子序列数据对感兴趣区域(LOD>1.9)进行精细定位。
我们在15号染色体上观察到第二个主成分有一个显著的LOD分数(LOD分数 = 3.01)以及12个提示性LOD分数。几个位点包含在全基因组关联研究(GWAS)中针对这些性状鉴定出的变异;然而,这些变异并不能解释连锁峰,其他常见变异也不能。在应用多重检验校正后,外显子序列数据鉴定出两个相关变异。
我们没有发现能解释这些连锁信号的常见单核苷酸多态性(SNP)。外显子测序在11号染色体上的MAPK3K11中发现了一个相对罕见的变异(MAF = 0.01),这有助于解释在第一个主成分中观察到的提示性连锁峰。条件分析显示,MAP3K11的LOD从2.01降至0.88,表明该变异可能部分解释了该染色体位置的连锁信号。MAP3K11与JNK途径相关,是一种促凋亡激酶,在包括LVH在内的各种病理状态下的心肌细胞凋亡诱导中起重要作用。