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Cloettapreis_2013_Nr_41

20 genetic association studies. Indeed, in 2003 two articles supported the notion that the candidate gene approach is promising by showing that functional gene variants, so called single nucleotide polymorphisms (SNPs, see Glossary), in the genes encoding the 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A) and the brain-derived neurotrophic fac- tor (BDNF) are associated with episodic memory performance15, 16 . Both molecules are highly expressed in the hippocampus and the cerebral cor- tex and have been implicated in animal learning and memory17-19 . In ­humans, a common HTR2A SNP predicts an amino acid substitution (His to Tyr) at residue 452 (H452Y). Compared with carriers of the common His/His variant, heterozygous (His/Tyr) carriers show a blunted receptor response upon pharmacological stimulation with serotonin20, 21 and poo- rer episodic memory performance in verbal and figural tasks15 . BDNF harbors a SNP which is located in the 5’ pro-BDNF sequence and results in a Valine to Methionine substitution at codon 66. The Met allele is ­related to deficits in the cellular distribution and regulated secretion of BDNF and to poorer episodic memory performance22 . The demonstra­- t­ion of successful identification of episodic memory-related molecules through the candidate gene approach prompted subsequent studies, which reported on such additional genes related to this cognitive capacity. Al­ though the majority of these studies remain to be independently replicat­ ed, they do suggest that focusing on pre-existing and well-established biological information may lead to the identification of genes related to episodic memory in humans. Genome-wide association studies (GWAS) While pre-existing biological information clearly facilitates the search for biologically meaningful candidates, it may on the other hand intro- duce a severe bias towards readily accessible molecular pathways and it definitely limits the potential of genetic association studies to identify novel genes and molecular pathways. Recent advances in the develop- ment of high-density genotyping platforms and analytical software now allow for high-resolution GWAS, which screen for association between heritable traits and millions of genetic variants distributed over the ­entire genome. This dense screening feature renders GWAS particularly useful in discovering novel molecular pathways of genetically complex traits.

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