Smeland Olav B, Andreassen Ole A
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Scand J Psychol. 2018 Feb;59(1):26-31. doi: 10.1111/sjop.12407.
Despite the consistent finding that cognitive dysfunction is a core characteristic of schizophrenia (SCZ), little is known about the underlying pathophysiology. Recent progress in human genetics, driven by large genome-wide association studies (GWAS), has provided new data about the genetic architecture of complex human traits, including cognition and SCZ. Novel analytical tools have provided unprecedented opportunities to leverage the large amount of information from GWAS. Here we review the latest findings related to genetic architecture and risk genes of SCZ and cognitive functions, and recent findings of overlapping genetic factors. The recent GWAS of SCZ implicate over 100 risk gene loci, each with a small effect. A similar genetic architecture seems to be present in cognitive domains, suggesting that these phenotypes are highly polygenic. Further, GWAS have revealed more than 20 gene loci associated with cognitive traits, including intelligence, general cognition (g-factor), reaction time and verbal-numerical reasoning. Several gene loci have been implicated in educational attainment, a proxy measure of cognitive function. Recently, overlapping gene loci were found between education and SCZ, and between SCZ and cognitive traits, suggesting common genetic risk between SCZ and cognitive dysfunction. Mathematical modeling of GWAS of cognition and SCZ indicate that only a fraction of the heritability is identified. The evidence suggests a polygenic architecture for SCZ and cognitive functions, and a large degree of shared genetic risk. This indicates novel molecular genetic mechanisms and strengthens the notion that SCZ is more likely a part of the normal distribution and not a separate entity.
尽管一直以来都发现认知功能障碍是精神分裂症（SCZ）的核心特征，但对其潜在的病理生理学却知之甚少。在大型全基因组关联研究（GWAS）的推动下，人类遗传学领域的最新进展为包括认知和SCZ在内的复杂人类性状的遗传结构提供了新数据。新型分析工具为利用GWAS中的大量信息提供了前所未有的机会。在此，我们综述了与SCZ的遗传结构、风险基因以及认知功能相关的最新研究结果，以及重叠遗传因素的近期研究发现。近期对SCZ的GWAS研究发现了100多个风险基因位点，每个位点的影响都很小。认知领域似乎也存在类似的遗传结构，这表明这些表型具有高度多基因性。此外，GWAS还揭示了20多个与认知性状相关的基因位点，包括智力、一般认知（g因素）、反应时间和言语数字推理。有几个基因位点与教育程度有关，而教育程度是认知功能的一种替代指标。最近，在教育与SCZ之间以及SCZ与认知性状之间发现了重叠的基因位点，这表明SCZ与认知功能障碍之间存在共同的遗传风险。对认知和SCZ的GWAS进行数学建模表明，仅识别出了部分遗传力。证据表明SCZ和认知功能具有多基因结构，且存在很大程度的共同遗传风险。这表明了新的分子遗传机制，并强化了SCZ更可能是正态分布的一部分而非独立实体的观念。
