Genetic variations related to maternal whole blood mitochondrial DNA copy number: a genome-wide and candidate gene study

We conducted genome-wide (GWAS) and candidate gene association studies of maternal mitochondrial DNA copy number. Maternal peripheral blood was collected during labor and delivery admission from 471 participants of a placental abruption case-control study conducted in Lima, Peru. Single nucleotide polymorphism (SNP) genotyping was performed using the Illumina Cardio-Metabo Chip. Whole blood mitochondrial DNA (mtDNA) copy number was measured using qRT-PCR techniques. We evaluated 119,629 SNPs in the GWAS and 161 SNPs (in 29 mitochondrial biogenesis and oxidative phosphorylation genes) in the candidate association study. Top hits from GWAS and the candidate gene study were selected to compute weighted genetic risk scores (wGRS). Linear regression models were used to calculate effect size estimates and related nominal <i>p</i> values. The top hit in our GWAS was chr19:51063065 in FOXA3 (empirical <i>p</i> values = 2.20e − 6). A total of 134 SNPs had <i>p</i> values p values = 6.32e − 6) and chr19:51083059 in MYPOP (<i>p</i> values = 3.23e − 5). In the candidate association study, several SNPs in PPARG, PRKCA, SP1 and THRB were associated with mtDNA copy number (<i>p</i> values β = 0.49, 95% CI:0.38–0.60, <i>p</i>

本研究针对母体线粒体DNA拷贝数开展了全基因组关联研究（Genome-Wide Association Study, GWAS）与候选基因关联研究。研究对象为秘鲁利马一项胎盘早剥病例对照研究中的471名参与者，于其分娩入院时采集产妇外周血样本。采用Illumina心血管代谢芯片完成单核苷酸多态性（Single Nucleotide Polymorphism, SNP）基因分型；通过实时定量聚合酶链反应（qRT-PCR）技术检测全血线粒体DNA（mitochondrial DNA, mtDNA）拷贝数。本研究在全基因组关联分析中纳入119629个SNP，在候选基因关联研究中纳入29个线粒体生物发生与氧化磷酸化相关基因内的161个SNP。选取全基因组关联研究与候选基因研究中的显著关联位点，计算加权遗传风险评分（weighted Genetic Risk Score, wGRS）；采用线性回归模型计算效应量估计值及相关名义p值。本研究全基因组关联分析中的最显著关联位点为FOXA3基因内的chr19:51063065（经验p值=2.20×10^-6）；另有134个SNP的p值为6.32×10^-6，以及MYPOP基因内的chr19:51083059（p值=3.23×10^-5）。在候选基因关联研究中，PPARG、PRKCA、SP1及THRB基因内的多个SNP与mtDNA拷贝数存在关联（β=0.49，95%置信区间：0.38~0.60，p值