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.
Highlights
Interindividual variations of memory performance in humans are regulated by genetic and non-genetic factors
genome-wide association studies (GWAS) OF EPISODIC AND WORKING MEMORY PERFORMANCE IN HUMANS The GWAS analyses on 13 episodic and working memory traits in up to 1318 individuals from the subgroup of BASE-II participants aged 60 years or older revealed 28 distinct genomic regions showing association P-values at 1 × 10−6 or below (Supplementary Table 2), indicating that at least some of these are genetically linked to human memory performance
The three most significant findings showed P-values at or below 1 × 10−7 and were observed with single nucleotide polymorphisms (SNPs) rs9882688 (P = 7.8 × 10−9 on chr 3p21.32) for trait “WL_save”, with rs1016365 (P = 9.7 × 10−8 on www.frontiersin.org chr 8q13.3) for “ItemItem”, and with rs113948889 (P = 9.9 × 10−8 on chr 12p13.33) for “TFEUWC”
Summary
Interindividual variations of memory performance in humans are regulated by genetic and non-genetic factors. Estimates from twin studies suggest that approximately half of the phenotypic variance is attributable to heritable factors, while the remainder reflects shared and non-shared environmental factors (McClearn et al, 1997). WWC1 is located on chromosome (chr) 5q34 and was identified nearly a decade ago in a GWAS on episodic memory in ∼300 subjects in which the lead SNP (rs17070145) showed evidence for genome-wide significant association (Papassotiropoulos et al, 2006). A number of other candidate genes have been tested in non-GWAS association studies, some suggesting evidence for an increased effect sizes when comparing older vs. younger adults (Li et al, 2013; Papenberg et al, 2014)
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