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ePaper created 2015-06-30, 14:11:35 | version 1.39.0
19 • Reliable and valid phenotypic assessment: Episodic memory per formance can be quantified by using reliable and valid instruments. Episodic memory is not a single phenotype, but instead may show distinct molecular profiles, depending on the specific episodic mem ory task (e.g., word list vs. story recall). • Control for episodic memory-unrelated phenotypes: Factors such as attention, concentration, and motivation may influence episodic mem ory performance and may bias genetic association findings. Con trolling for episodic memory-unrelated phenotypes is therefore crucial. • Specific neural correlates: Episodic memory has well definable and well quantifiable neural correlates (e.g., memory-related activity of the hippocampus and parahippocampal gyrus). This allows for further corroboration of genetic association findings at the neural systems level. • Independent replication: Regardless of the statistical models used and however simple or complicated they might be, successful gene iden- tification stands and falls with independent replication of the gene- phenotype associations. This is particularly important in the era of genome-wide studies (GWAS), which screen for association between heritable traits and millions of genetic variants distributed over the entire genome, thereby introducing a multiple testing burden. Genetic association studies with candidate genes Whenever sufficient knowledge about the biological mechanisms under- lying the physiology (and in case of disease, the pathophysiology) of a certain trait exists, candidate gene association studies, which assess the correlation between one or more variants of a biologically plausible gene (or a set of genes) with the phenotype, may be readily implemented. In the case of episodic memory, sufficient biological knowledge does exist. A number of animal studies have identified genes and signaling mole cules important for memory, including protein kinases and phosphatases, transcription factors, growth factors, and receptor complexes1-5 . These studies suggest that molecules related to learning-related synaptic plas- ticity, long-term potentiation (LTP), long-term depression (LTD), and ac- tivity of such brain structures as the hippocampus, parahippocampal gyrus, and the amygdala might represent ideal biological candidates for