Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
PLoS One. 2011;6(12):e29337. doi: 10.1371/journal.pone.0029337. Epub 2011 Dec 21.
Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed "missing heritability." The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (P(nominal combined)=0.000001). The epistatic interaction was robust, as it was significant in a screening (P(nominal)=0.0000012) and in a replication sample (P(nominal)=0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (P(nominal)=0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits.
尽管目前在高通量、密集的基因组扫描方面取得了进展，但复杂特征遗传率的很大一部分仍然无法解释，这种现象通常被称为“遗传缺失”。忽视了分析方法来解释基因-基因相互作用效应，如统计上位性，可能是造成这种现象的核心原因。在这里，我们对人类情景记忆进行了全面的双向 SNP 相互作用分析，情景记忆是一种可遗传的复杂特征，并集中在 120 个已知在大鼠海马体中表现出差异、与记忆相关的表达模式的基因上。功能性磁共振成像也用于捕捉与记忆相关的大脑活动中的基因型依赖性差异。在位于钾通道基因（KCNB2 和 KCNH5）中的两个标记物之间观察到与情景记忆相关的显著相互作用（P(nominal combined)=0.000001）。上位性相互作用是稳健的，因为在筛选（P(nominal)=0.0000012）和复制样本（P(nominal)=0.01）中均具有统计学意义。最后，我们发现海马旁回中的基因型依赖性活动差异（P(nominal)=0.001）支持行为遗传学的发现。我们的结果表明，对于复杂特征的分析方法需要超越单一标记物统计分析，这一点非常重要。
