title: MicroRNA-138 is a potential regulator of memory performance in humans.
abstract: Genetic factors underlie a substantial proportion of individual differences in cognitive functions in humans, including processes related to episodic and working memory. While genetic association studies have proposed several candidate "memory genes," these currently explain only a minor fraction of the phenotypic variance. Here, we performed genome-wide screening on 13 episodic and working memory phenotypes in 1318 participants of the Berlin Aging Study II aged 60 years or older. The analyses highlight a number of novel single nucleotide polymorphisms (SNPs) associated with memory performance, including one located in a putative regulatory region of microRNA (miRNA) hsa-mir-138-5p (rs9882688, P-value = 7.8 × 10(-9)). Expression quantitative trait locus analyses on next-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines (P-value = 5 × 10(-4)). In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3' untranslated region (3' UTR) of DCP1B, a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3' UTR reporter constructs in two human cell lines (HEK293: P-value = 0.0470; SH-SY5Y: P-value = 0.0866). Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo. In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory function.
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany ; Charité Research Group on Geriatrics, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors: Julia
authors: J
authors: Schröder
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany.
authors: Sara
authors: S
authors: Ansaloni
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany ; Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology Berlin, Germany.
authors: Marcel
authors: M
authors: Schilling
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany ; Center for Lifespan Psychology, Max Planck Institute for Human Development Berlin, Germany.
authors: Tian
authors: T
authors: Liu
authors: Department of Neuropathology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors: Josefine
authors: J
authors: Radke
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany.
authors: Marian
authors: M
authors: Jaedicke
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany.
authors: Brit-Maren M
authors: BM
authors: Schjeide
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany.
authors: Andriy
authors: A
authors: Mashychev
authors: Charité Research Group on Geriatrics, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors: Christina
authors: C
authors: Tegeler
authors: Department of Neuropathology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors: Helena
authors: H
authors: Radbruch
authors: Center for Lifespan Psychology, Max Planck Institute for Human Development Berlin, Germany ; Aging Research Center, Karolinska Institute Stockholm, Sweden.
authors: Goran
authors: G
authors: Papenberg
authors: Center for Lifespan Psychology, Max Planck Institute for Human Development Berlin, Germany.
authors: Sandra
authors: S
authors: Düzel
authors: Charité Research Group on Geriatrics, Charité - Universitätsmedizin Berlin Berlin, Germany ; Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors: Ilja
authors: I
authors: Demuth
authors: Charité Research Group on Geriatrics, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors: Nina
authors: N
authors: Bucholtz
authors: Center for Lifespan Psychology, Max Planck Institute for Human Development Berlin, Germany.
authors: Ulman
authors: U
authors: Lindenberger
authors: Center for Lifespan Psychology, Max Planck Institute for Human Development Berlin, Germany ; Department of Psychology, Lifespan Developmental Neuroscience, TU Dresden Dresden, Germany.
authors: Shu-Chen
authors: SC
authors: Li
authors: Charité Research Group on Geriatrics, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors: Elisabeth
authors: E
authors: Steinhagen-Thiessen
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany ; Focus Program Translational Neuroscience, Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz Mainz, Germany.
authors: Christina M
authors: CM
authors: Lill
authors: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics Berlin, Germany ; Faculty of Medicine, School of Public Health, Imperial College London London, UK.
authors: Lars
authors: L
authors: Bertram
keywords: DCP1B; GWAS; episodic memory; genome-wide association study; hsa-mir-138-5p; microRNA; working memory