The dystrophin gene and cognitive function in the general population

Area of Science:

• Neurogenetics
• Human Genetics
• Cognitive Neuroscience

Background:

• The dystrophin gene (DMD) is crucial for muscle function, but its role in cognitive variability in healthy populations is less understood.
• Single-nucleotide variants (SNVs) within genes can influence complex traits, including cognitive abilities.

Purpose of the Study:

• To investigate the association between single-nucleotide variants in the dystrophin gene (DMD) and cognitive function variability in healthy adults.
• To explore both individual variant effects and the overall gene-based association of DMD with cognitive traits.

Main Methods:

• Analysis of exome sequencing data from 1240 participants (Erasmus Rucphen family study) and 1464 individuals (Rotterdam Study).
• Linear (mixed) modeling adjusted for age, sex, and education to assess associations between DMD variants and cognitive traits.
• Sequence Kernel Association Test (SKAT) to evaluate the overall association of rare variants within the DMD gene with cognitive performance.

Main Results:

• No single DMD variant met the stringent genome-wide significance threshold (P<1 × 10(-4)).
• Variant rs147546024:A>G showed a strong association with the block-design test (P=2.56 × 10(-4)) in the ERF cohort.
• Variant rs1800273:G>A exhibited a suggestive association with the Mini-Mental State Examination (P=0.002) in the RS cohort. Gene-based analysis indicated suggestive associations (P=0.087, P=0.074) with general cognitive ability.

Conclusions:

• Single-nucleotide variants and overall gene-based analyses suggest that the dystrophin gene (DMD) may harbor variants influencing cognitive functioning in the general population.
• While no single variant reached genome-wide significance, specific variants and the gene overall show potential links to cognitive variability.