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Cloettapreis_2013_Nr_41

21 The first GWAS on episodic memory identified KIBRA and CLSTN2 as episodic memory-related genes23 . Replication studies in European and Asian populations further supported the role of KIBRA in episodic mem­ ory (e.g.,24-27 ). Importantly, a study in two large Scottish samples sug­ gested that KIBRA is related to processes specific to the conscious recall of item-based material, possibly reflecting hippocampal processing24 . This high degree of specificity underscores the importance of precise phenotypic assessment in behavioral genetic research, including replica- tion studies. Subsequent GWAS in healthy participants supported the role of additional genes such as CAMTA128 and NRXN129 in episodic memo- ry performance by using a variety of neuropsychological measurements. It is important to stress that the genes identified through genome-wide screening are involved in memory-related molecular pathways such as protein phosphorylation, calcium-responsive transcriptional activation, and – in general – synaptic plasticity. Nevertheless, it is highly unlikely that most of these genes would have been selected a priori in a candi­- date gene setting, simply because very little was known regarding the biological relevance of these genes prior to their identification in the course of the GWAS. This demonstrates the substantial potential of this approach for the identification of novel genes and pathways related to human ­episodic memory. Our knowledge about the molecular underpin- nings of this trait has already increased and it will undoubtedly continue to increase as larger and denser GWAS, utilizing refined analytical ­methodology, are expected in the near future. Genetic complexity GWAS may powerfully identify components of the genetic basis of com- plex, multigenic traits. In the past few years, GWAS using hundreds of thousands and even millions of polymorphic markers, mainly SNPs, in samples ranging from a few hundreds to several thousands of individu- als have led and still lead to the identification of numerous susceptibility genes and trait-related genomic variants. However, despite this exten­- sive use of genetic and analytical force, which has undoubtedly proven successful, a major portion of the heritability of complex traits still ­remains unexplained, a phenomenon commonly termed «missing herita- bility»30 .

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