Hatzimanolis Alex, Bhatnagar Pallav, Moes Anna, Wang Ruihua, Roussos Panos, Bitsios Panos, Stefanis Costas N, Pulver Ann E, Arking Dan E, Smyrnis Nikolaos, Stefanis Nicholas C, Avramopoulos Dimitrios
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Am J Med Genet B Neuropsychiatr Genet. 2015 Jul;168B(5):392-401. doi: 10.1002/ajmg.b.32323. Epub 2015 May 12.
Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.
神经认知能力构成了具有相当高遗传度的复杂性状。精神分裂症（SZ）患者通常会出现神经认知受损，而越来越多的证据表明神经认知与SZ之间存在共同的遗传决定因素。在此，我们报告了一项针对与SZ相关的神经心理学和动眼神经特征的全基因组关联研究（GWAS），该研究在一个健康年轻男性的普通人群样本（n = 1079）中进行。在一个具有相同表型的内部样本（n = 738）和一个具有可比神经心理学测量值的年轻男性独立队列（n = 825）中进行了后续基因分型。基于全基因组单核苷酸多态性（SNP）确定遗传度估计值，并在人脑样本中评估对基因表达的潜在调控作用。利用认知基因组学联盟（COGENT）和精神疾病基因组学联盟（PGC-SZ）的荟萃分析GWAS结果，测试了与一般认知能力和SZ风险多基因评分的相关性。GWAS结果表明，编码参与突触神经传递的蛋白质靶点的生物学相关基因座存在关联，尽管未检测到有力的个体复制结果，因此需要进一步验证。基于置换的二次分析显示，在GWAS排名靠前的信号中，言语工作记忆（WM）和反扫视受试者内反应时间变异性存在过多强关联位点（经验P < 0.001），提示存在多个真正的单SNP阳性关联。观察到WM表现具有显著的遗传度。此外，持续注意力/警觉性和WM与COGENT和PGC-SZ得出的多基因评分均存在提示性关联。总体而言，这些结果表明，常见的基因变异解释了年轻人神经认知功能的部分变异性，尤其是WM，并提供了支持性证据，即SZ遗传风险增加预示着普通人群中的神经认知波动。
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