The dystrophin gene and cognitive function in the general population

Abstract

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (Po1 × 10 − 4 ), rs147546024:A4G showed strong association (β = 1.786, P-value = 2.56 × 10 − 4 ) with block-design test in the ERF study, while another variant rs1800273:G4A showed suggestive association (β = − 0.465, P-value = 0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A4G is an intronic variant, whereas rs1800273:G4A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values = 0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.

Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes

“…In all, the brain dystrophin Dp427 appears to play a role during acquisition of associative learning as well as in general processes involved in memory consolidation. This is in accordance with recent single variant and gene-based analyses showing that dmd-gene variants affecting this full-length brain dystrophin are associated with general variability of cognitive ability in healthy human populations (Vojinovic et al, 2014).…”

Genetic effects and gene-by-education interactions on episodic memory performance and decline in an aging population

“…In addition, 3 genes (ABCA7, SLC24A4, SORL1) had a nominally significant interaction with education on memory performance/ decline (p<0.05), and 3 genes (BIN1, CELF1, CR1) were suggestively associated with memory performance/decline (p<0.1) in at least one ethnic group in our study, suggesting that we were able to replicate some of the previous findings implicating Alzheimer's Disease-associated genes in longitudinal assessment of cognitive decline. The final study applied SKAT to exome sequencing data collected from over 2,500 participants in a single gene (DMD) and cognition (Vojinovic, et al, 2015). This gene was not among those that we evaluated.…”

Computational cognitive modeling and validation of Dp140 induced alteration of working memory in Duchenne Muscular Dystrophy

“…Whether variation in dystrophin expression pattern, affects cognitive domains in phenotypically normal population, has remained an outstanding question. One study reported the role of single nucleotide DMD variants (rs147546024:A > G, an intronic variant; rs1800273:G > A, a missense variant) in cognitively healthy general population 21 . A case study reported manifestation of intellectual disability without usual muscular dystrophy phenotype due to deletion of three base pairs (c.9711_9713del) in the distal region of DMD gene 22 , providing substantial evidence regarding DMD distal region's association with human cognition.…”