Statistical epistasis and functional brain imaging support a role of voltage-gated potassium channels in human memory.
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.
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland. angela.heck@unibas.ch
Angela
A
Heck
Christian
C
Vogler
Leo
L
Gschwind
Sandra
S
Ackermann
Bianca
B
Auschra
Klara
K
Spalek
Björn
B
Rasch
Dominique
D
de Quervain
Andreas
A
Papassotiropoulos
D001921:Brain / Q000502:physiology*; D004843:Epistasis, Genetic; D006801:Humans; D015640:Ion Channel Gating; D008279:Magnetic Resonance Imaging; D008568:Memory; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000502:physiology*
D015221:Potassium Channels