Statistical epistasis and functional brain imaging support a role of voltage-gated potassium channels in human memory.

• Main Authors: Angela Heck, Christian Vogler, Leo Gschwind, Sandra Ackermann, Bianca Auschra, Klara Spalek, Björn Rasch, Dominique de Quervain, Andreas Papassotiropoulos
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2011-01-01
• Series: PLoS ONE
• Online Access: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22216252/pdf/?tool=EBI

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.