Unit of Genomic of Complex Diseases, Institute of Biomedical Research of Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
PLoS One. 2012;7(8):e42711. doi: 10.1371/journal.pone.0042711. Epub 2012 Aug 20.
Altered mitochondrial DNA (mtDNA) levels have been associated with common diseases in humans. We investigated the genetic mechanism that controls mtDNA levels using genome-wide linkage analyses in families from the Genetic Analysis of Idiopathic Thrombophilia Project (GAIT). We measure mtDNA levels by quantitative real-time PCR in 386 subjects from 21 extended Spanish families. A variance component linkage method using 485 microsatellites was conducted to evaluate linkage and to detect quantitative trait loci (QTLs) involved in the control of mtDNA levels. The heritalibility of mtDNA levels was 0.33 (p=1.82e-05). We identified a QTL on Chromosome 2 (LOD=2.21) using all of the subjects, independently on their sex. When females and males were analysed separately, three QTLs were identified. Females showed the same QTL on Chromosome 2 (LOD=3.09), indicating that the QTL identified in the analysis using all of the subjects was a strong female QTL, and another one on Chromosome 3 (LOD=2.67), whereas in males a QTL was identified on Chromosome 1 (LOD=2.81). These QTLs were fine-mapped to find associations with mtDNA levels. The most significant SNP association was for the rs10888838 on Chromosome 1 in males. This SNP mapped to the gene MRPL37, involved in mitochondrial protein translation. The rs2140855 on Chromosome 2 showed association in the analysis using all of the subjects. It was near the gene CMPK2, which encodes a mitochondrial enzyme of the salvage pathway of deoxyribonucleotide synthesis. Our results provide evidence of a sex-specific genetic mechanism for the control of mtDNA levels and provide a framework to identify new genes that influence mtDNA levels.
线粒体 DNA（mtDNA）水平的改变与人类常见疾病有关。我们使用来自遗传性易栓症分析项目（GAIT）的家族的全基因组连锁分析来研究控制 mtDNA 水平的遗传机制。我们在 21 个扩展的西班牙家族的 386 名受试者中通过定量实时 PCR 测量 mtDNA 水平。使用 485 个微卫星的方差分量连锁方法进行连锁分析，并检测参与 mtDNA 水平控制的数量性状基因座（QTL）。mtDNA 水平的遗传力为 0.33（p=1.82e-05）。我们在所有受试者中（独立于其性别）在染色体 2 上鉴定出一个 QTL（LOD=2.21）。当分别分析女性和男性时，鉴定出三个 QTL。女性在染色体 2 上显示出相同的 QTL（LOD=3.09），表明在使用所有受试者进行的分析中鉴定出的 QTL 是一个强的女性 QTL，以及另一个在染色体 3 上（LOD=2.67），而在男性中鉴定出一个 QTL 在染色体 1 上（LOD=2.81）。这些 QTL 被精细定位以找到与 mtDNA 水平的关联。在男性中，与染色体 1 上的 rs10888838 最显著的 SNP 关联。该 SNP 映射到参与线粒体蛋白翻译的基因 MRPL37。在使用所有受试者的分析中，染色体 2 上的 rs2140855 显示出关联。它靠近编码脱氧核苷酸合成补救途径中的线粒体酶的基因 CMPK2。我们的研究结果为 mtDNA 水平控制的性别特异性遗传机制提供了证据，并为鉴定影响 mtDNA 水平的新基因提供了框架。
