Tabb Keri L, Hellwege Jacklyn N, Palmer Nicholette D, Dimitrov Latchezar, Sajuthi Satria, Taylor Kent D, Ng Maggie C Y, Hawkins Gregory A, Chen Yii-der Ida, Brown W Mark, McWilliams David, Williams Adrienne, Lorenzo Carlos, Norris Jill M, Long Jirong, Rotter Jerome I, Curran Joanne E, Blangero John, Wagenknecht Lynne E, Langefeld Carl D, Bowden Donald W
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Ann Hum Genet. 2017 Mar;81(2):49-58. doi: 10.1111/ahg.12184. Epub 2017 Jan 9.
Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P < 5 × 10 ), with the strongest association between rs651821:C>T in APOA5 and triglyceride levels (P = 3.67 × 10 ). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.
基于家系的方法是在大家庭中识别界定性状的遗传变异的一种潜在有力工具，特别是当用于补充传统关联分析时。我们利用两点连锁分析和单变异关联分析来评估来自胰岛素抵抗动脉粥样硬化家系研究的1205名西班牙裔美国人（78个家系）的全外显子组测序（WES）数据。WES在次要等位基因频率阈值≥0.005之上鉴定出211,612个变异。在进行质量控制检查后，对这些变异进行连锁和/或与50种心脏代谢性状的关联检测。两点连锁分析产生了10,580,600个优势对数（LOD）分数，其中1148个LOD分数≥3，183个LOD分数≥4，29个LOD分数≥5。rs2289043:T>C （位于UNC5C基因）与皮下脂肪组织体积的最大新LOD分数为5.50。关联分析鉴定出13个达到全基因组显著性（P < 5×10⁻⁸）的变异，其中APOA5基因中的rs651821:C>T与甘油三酯水平的关联最强（P = 3.67×10⁻¹²）。总体而言，与该人群中的外显子芯片分析相比，WES检测到的信息性变异数量增加了5.2倍，其中近30%相对于单核苷酸多态性数据库（dbSNP）构建版本138是新变异。因此，整合来自WES数据的两点连锁和单变异关联分析结果能够识别可能影响心脏代谢性状的新信号。
