Gonçalves Vanessa F, Giamberardino Stephanie N, Crowley James J, Vawter Marquis P, Saxena Richa, Bulik Cynthia M, Yilmaz Zeynep, Hultman Christina M, Sklar Pamela, Kennedy James L, Sullivan Patrick F, Knight Jo
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
PLoS One. 2018 Jan 25;13(1):e0191153. doi: 10.1371/journal.pone.0191153. eCollection 2018.
Oxidative phosphorylation within mitochondria is the main source of aerobic energy for neuronal functioning, and the key genes are located in mitochondrial DNA. Deficits in oxidative phosphorylation functioning have been reported for schizophrenia, but efforts in the identification of genetic markers within the mitochondrial DNA that predispose to schizophrenia have been limited. We genotyped a set of mitochondrial SNPs using Illumina HumanExome arrays and tested for association in the Swedish schizophrenia sample (N> 10,000). We developed a novel approach for mitochondrial DNA imputation in order to increase the number of common SNPs available for association analysis. The most significant findings were for the mitochondrial SNPs C15452A (GRCh38.p10; rs527236209; p = 0.007; gene MT-CYB; defining haplogroup JT); A11251G (rs869096886; p = 0.007; gene MT-ND4; defining haplogroup JT), and T4216C (rs1599988; p = 0.008, gene MT-ND1, defining haplogroup R2'JT). We also conducted rare variant burden analyses and obtained a p-value of 0.007. For multimarker haplotypes analysis, the most significant finding was for the J group (OR: 0.86, p = 0.02). We conducted the largest association study of mitochondrial DNA variants and schizophrenia but did not find an association that survived multiple testing correction. Analysis of a larger sample is required and will allow a better understanding of the role of mitochondria in schizophrenia.
线粒体中的氧化磷酸化是神经元功能有氧能量的主要来源，关键基因位于线粒体DNA中。已有报道称精神分裂症患者存在氧化磷酸化功能缺陷，但在线粒体DNA中鉴定易患精神分裂症的遗传标记的工作一直有限。我们使用Illumina HumanExome阵列对一组线粒体单核苷酸多态性（SNP）进行基因分型，并在瑞典精神分裂症样本（N>10,000）中进行关联测试。我们开发了一种新的线粒体DNA插补方法，以增加可用于关联分析的常见SNP数量。最显著的发现是线粒体SNP C15452A（GRCh38.p10；rs527236209；p = 0.007；基因MT-CYB；定义单倍群JT）；A11251G（rs869096886；p = 0.007；基因MT-ND4；定义单倍群JT），以及T4216C（rs1599988；p = 0.008，基因MT-ND1，定义单倍群R2'JT）。我们还进行了罕见变异负担分析，获得的p值为0.007。对于多标记单倍型分析，最显著的发现是J组（比值比：0.86，p = 0.02）。我们进行了最大规模的线粒体DNA变异与精神分裂症的关联研究，但未发现经多重检验校正后仍存在的关联。需要分析更大的样本，以便更好地理解线粒体在精神分裂症中的作用。
