Erk S, Mohnke S, Ripke S, Lett T A, Veer I M, Wackerhagen C, Grimm O, Romanczuk-Seiferth N, Degenhardt F, Tost H, Mattheisen M, Mühleisen T W, Charlet K, Skarabis N, Kiefer F, Cichon S, Witt S H, Nöthen M M, Rietschel M, Heinz A, Meyer-Lindenberg A, Walter H
Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Transl Psychiatry. 2017 Jan 10;7(1):e997. doi: 10.1038/tp.2016.272.
Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (P=0.047) and social cognition (P=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (P=1.63 × 10, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; P<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.
最近，确定了125个在全基因组水平上支持与精神分裂症相关联的基因座。我们研究了这些变异及其累积遗传风险对研究领域标准（RDoC）的五个神经认知领域（工作记忆、奖赏处理、情景记忆、社会认知和情绪处理）中大脑激活的影响。在578名健康受试者中，我们测试了（i）一个多基因风险谱评分（RPS）的关联性，该评分包括在最近的全基因组关联研究（GWAS）荟萃分析中达到全基因组显著性的所有单核苷酸多态性（SNP），以及（ii）所有独立的全基因组显著基因座的关联性，这些基因座在我们的样本中显示出所有等位基因组的充分分布（105个SNP）。RPS分别在情景记忆（P = 0.047）和社会认知（P = 0.025）过程中与膝周前扣带回和后扣带回/楔前叶激活呈名义上的关联。单SNP分析显示，位于EP300附近的rs9607782与情绪处理过程中杏仁核的激活显著相关（P = 1.63×10，超过了对SNP数量的Bonferroni校正）。重要的是，这种关联在一个独立样本中是可重复的（N = 150；P < 0.025）。其他先前与成像表型相关的SNP效应呈名义上的显著性，但在对所测试的SNP数量进行校正后并不显著。为了评估我们的数据中是否存在真实信号，我们用105个随机选择的与精神分裂症无关的变异重复了单SNP分析，观察到显著结果较少且关联概率较低。应用严格的方法程序，我们发现了初步证据支持rs9607782赋予的精神分裂症遗传风险可能由杏仁核功能介导这一观点。我们批判性地评估了所采用方法的潜在注意事项，并为未来研究提供了建议。
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