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Twin studies have revealed that memory and relatedbrain functions are highly heritable traits, but putative candidate geneshave shown small and inconsistent effects -referred to as "the missing heritability". Little is known about the combined effect of several genes onbrain function: whether the presence of one "risk" variant hides the effect ofanother, interacts with it, or increases the risk in an additive -or even multiplicative -way. In a large fMRI sample we explored the combined effect ofpolymorphisms with documented impact on brain activation in the medialtemporal lobe (MTL) during episodic memory encoding or retrieval. Analyses of the effects of individual genes revealed decreased MTL activationfor ApoE £4 and BDNF Met alíeles during encoding, and for Kibra CCand the CLSTN2 T alíele during retrieval. Analyses of combined effectsrevealed that, during encoding, carriers of both the ApoE £4 and the BDNFMet alíele had lowest MTL activation, whereas non<arriers of both alíeleshad the highest activation in several MTL clusters. For most clusters, stepwise regression analyses revealed that the addifion of a second polymorphism increased the percentage of explained variance in BOLD signal. Similar clusters were seen for the combination of Kibra and CLSTN2 genotypes during refi-ieval, but here the difference in BOLD activafion was mainly driven by one of the polymorphisms. In conclusion, our results highlight the importance of simultaneously considering several genefic variants.