Supplementary Material for: Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

<br>Genetic evidence has supported the hypothesis that schizophrenia (SZ) is a polygenic disorder caused by the disruption in function of several or many genes. The most common and reproducible cellular phenotype associated with SZ is a reduction in dendritic spines within the neocortex, suggesting alterations in dendritic architecture may cause aberrant cortical circuitry and SZ symptoms. Here, we review evidence supporting a multifactorial model of mitochondrial dysfunction in SZ etiology and discuss how these multiple paths to mitochondrial dysfunction may contribute to dendritic spine loss and/or underdevelopment in some SZ subjects. The pathophysiological role of mitochondrial dysfunction in SZ is based upon genomic analyses of both the mitochondrial genome and nuclear genes involved in mitochondrial function. Previous studies and preliminary data suggest SZ is associated with specific alleles and haplogroups of the mitochondrial genome, and also correlates with a reduction in mitochondrial copy number and an increase in synonymous and nonsynonymous substitutions of mitochondrial DNA. Mitochondrial dysfunction has also been widely implicated in SZ by genome-wide association, exome sequencing, altered gene expression, proteomics, microscopy analyses, and induced pluripotent stem cell studies. Together, these data support the hypothesis that SZ is a polygenic disorder with an enrichment of mitochondrial targets.

遗传证据已支持下述假说：精神分裂症（schizophrenia, SZ）是一类多基因疾病，由多个乃至众多基因的功能紊乱所导致。与精神分裂症关联最为普遍且可重复的细胞表型，为新皮层（neocortex）内树突棘（dendritic spines）数量减少，这提示树突结构异常可能引发皮层环路紊乱，并最终导致精神分裂症相关症状。本文综述了支持精神分裂症病因学（etiology）中线粒体功能异常（mitochondrial dysfunction）多因素模型的相关证据，并探讨了这些引发线粒体功能异常的多条通路如何导致部分精神分裂症患者出现树突棘丢失或发育不全的情况。线粒体功能异常在精神分裂症病理生理过程中的作用，基于针对线粒体基因组（mitochondrial genome）与参与线粒体功能的核基因（nuclear genes）的基因组学分析。既往研究与初步数据表明，精神分裂症与线粒体基因组的特定等位基因（alleles）及单倍群（haplogroups）存在关联，同时还与线粒体拷贝数（mitochondrial copy number）减少、线粒体DNA（mitochondrial DNA）同义替换（synonymous substitution）与非同义替换（nonsynonymous substitution）频率升高相关。全基因组关联分析（genome-wide association）、外显子组测序（exome sequencing）、基因表达异常、蛋白质组学（proteomics）、显微镜分析（microscopy analyses）以及诱导多能干细胞（induced pluripotent stem cell）研究，也已广泛证实线粒体功能异常与精神分裂症存在关联。综合上述所有研究数据，可支持如下假说：精神分裂症作为一种多基因疾病，其致病相关靶点存在线粒体富集现象。