Walton Esther, Geisler Daniel, Lee Phil H, Hass Johanna, Turner Jessica A, Liu Jingyu, Sponheim Scott R, White Tonya, Wassink Thomas H, Roessner Veit, Gollub Randy L, Calhoun Vince D, Ehrlich Stefan
Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;
The Mind Research Network, Albuquerque, NM;
Schizophr Bull. 2014 Nov;40(6):1263-71. doi: 10.1093/schbul/sbt174. Epub 2013 Dec 10.
Considering the diverse clinical presentation and likely polygenic etiology of schizophrenia, this investigation examined the effect of polygenic risk on a well-established intermediate phenotype for schizophrenia. We hypothesized that a measure of cumulative genetic risk based on additive effects of many genetic susceptibility loci for schizophrenia would predict prefrontal cortical inefficiency during working memory, a brain-based biomarker for the disorder. The present study combined imaging, genetic and behavioral data obtained by the Mind Clinical Imaging Consortium study of schizophrenia (n = 255). For each participant, we derived a polygenic risk score (PGRS), which was based on over 600 nominally significant single nucleotide polymorphisms, associated with schizophrenia in a separate discovery sample comprising 3322 schizophrenia patients and 3587 control participants. Increased polygenic risk for schizophrenia was associated with neural inefficiency in the left dorsolateral prefrontal cortex after covarying for the effects of acquisition site, diagnosis, and population stratification. We also provide additional supporting evidence for our original findings using scores based on results from the Psychiatric Genomics Consortium study. Gene ontology analysis of the PGRS highlighted genetic loci involved in brain development and several other processes possibly contributing to disease etiology. Our study permits new insights into the additive effect of hundreds of genetic susceptibility loci on a brain-based intermediate phenotype for schizophrenia. The combined impact of many common genetic variants of small effect are likely to better reveal etiologic mechanisms of the disorder than the study of single common genetic variants.
考虑到精神分裂症多样的临床表现和可能的多基因病因，本研究考察了多基因风险对一种已确立的精神分裂症中间表型的影响。我们假设，基于许多精神分裂症遗传易感性位点加性效应的累积遗传风险测量方法，能够预测工作记忆期间前额叶皮质功能低效，这是该疾病基于大脑的生物标志物。本研究结合了精神分裂症的心智临床成像联盟研究（n = 255）所获得的成像、基因和行为数据。对于每一位参与者，我们得出了一个多基因风险评分（PGRS），该评分基于在一个包含3322例精神分裂症患者和3587例对照参与者的独立发现样本中与精神分裂症相关的600多个名义上显著的单核苷酸多态性。在对采集部位、诊断和人群分层的影响进行协变量调整后，精神分裂症多基因风险增加与左侧背外侧前额叶皮质的神经功能低效相关。我们还使用基于精神疾病基因组学联盟研究结果的评分，为我们最初的发现提供了额外的支持证据。PGRS的基因本体分析突出了参与大脑发育以及可能导致疾病病因的其他几个过程的基因位点。我们的研究为数百个遗传易感性位点对精神分裂症基于大脑的中间表型的加性效应提供了新的见解。与单一常见遗传变异的研究相比，许多小效应常见遗传变异的综合影响可能更能揭示该疾病的病因机制。
