Lee P H, Baker J T, Holmes A J, Jahanshad N, Ge T, Jung J-Y, Cruz Y, Manoach D S, Hibar D P, Faskowitz J, McMahon K L, de Zubicaray G I, Martin N G, Wright M J, Öngür D, Buckner R, Roffman J, Thompson P M, Smoller J W
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mol Psychiatry. 2016 Dec;21(12):1680-1689. doi: 10.1038/mp.2016.164. Epub 2016 Oct 11.
Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.
精神分裂症是一种具有复杂遗传病因的毁灭性神经发育障碍。在患者和前驱样本中已观察到广泛的皮质灰质损失。然而，尚不清楚精神分裂症相关的皮质结构变异是由疾病病因引起还是疾病继发所致。在这里，我们使用基于分区的遗传力分析方法，对来自1750名健康个体的全基因组单核苷酸多态性（SNP）和神经影像数据进行分析，以解决这个问题。我们发现，与精神分裂症相关的基因变异在八种脑表型中解释了显著富集的性状遗传力比例（错误发现率=10%）。特别是，在不同的SNP选择条件下，颅内体积和左侧额上回厚度与精神分裂症遗传风险呈现出显著且稳健的关联。跨疾病比较表明，与精神分裂症相关的脑区神经遗传结构至少部分与其他精神疾病相同。我们的研究突出了普通人群中精神分裂症遗传风险的关键神经解剖学相关性。这些可能为该疾病复杂的病理生理学提供基本见解，并为塑造该疾病的神经认知缺陷提供潜在联系。
