title: 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 (P<1 × 10(-4)), rs147546024:A>G showed strong association (β = 1.786, P-value = 2.56 × 10(-4)) with block-design test in the ERF study, while another variant rs1800273:G>A 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:A>G is an intronic variant, whereas rs1800273:G>A 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.
authors.affiliation: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Clinic for Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Dina
authors.initials: D
authors.lastname: Vojinovic
authors.affiliation: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Hieab H H
authors.initials: HH
authors.lastname: Adams
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sven J
authors.initials: SJ
authors.lastname: van der Lee
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Ibrahim-Verbaas
authors.affiliation: Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Rutger
authors.initials: R
authors.lastname: Brouwer
authors.affiliation: Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Mirjam C G N
authors.initials: MC
authors.lastname: van den Hout
authors.affiliation: Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Oole
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Rooij
authors.affiliation: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands [3] Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, The Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.affiliation: 1] Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands [2] Center of Medical Systems Biology, Leiden, The Netherlands.
authors.forename: GertJan B
authors.initials: GB
authors.lastname: van Ommen
authors.affiliation: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands [3] Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, The Netherlands [3] Center of Medical Systems Biology, Leiden, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
mesh_terms: D000328:Adult; D003071:Cognition; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C484258:DMD protein, human; D016189:Dystrophin