Additive effect of BDNF and REST polymorphisms is associated with improved general cognitive ability

Area of Science:

• Neuroscience
• Genetics
• Cognitive Science

Background:

• Brain-derived neurotrophic factor (BDNF) influences neuronal functions, but its association with cognitive abilities is debated.
• Conflicting findings regarding the BDNF Val66Met polymorphism and cognition may stem from unexamined genetic interactions.
• The RE1-silencing transcription factor (REST) gene regulates BDNF expression, making it a candidate for modulating cognitive phenotypes.

Purpose of the Study:

• To investigate the association between polymorphisms in the REST gene and cognitive abilities.
• To examine the combined effects of REST and BDNF Val66Met polymorphisms on general intelligence in older adults.

Main Methods:

• Genotyping of REST gene polymorphisms, including a novel exon 4 hexadecapeptide VNTR and five SNPs, in 746 community-dwelling older volunteers.
• Analysis of REST genotypes independently and in conjunction with the BDNF Val66Met polymorphism.
• Statistical analysis to assess associations and interactions between genetic variations and cognitive performance scores.

Main Results:

• A specific REST gene haplotype, featuring a four-copy VNTR and a non-synonymous SNP, showed a weak but significant association with higher general intelligence (P=0.05).
• A significant interaction (P=0.0003) was observed between this REST haplotype and the BDNF Val66Met polymorphism, with an additive increase in cognitive performance for individuals with the BDNF Val66 allele and the specific REST haplotype (P=0.004).
• REST haplotypes did not exacerbate the cognitive effects of the BDNF Met66 polymorphism beyond its independent influence.

Conclusions:

• Genetic variations in the REST gene, particularly a haplotype with a four-copy VNTR, are associated with general intelligence.
• Investigating REST gene polymorphisms in conjunction with BDNF Val66Met is crucial for resolving conflicting findings on BDNF and cognition.
• Considering REST gene variations may improve the understanding of genetic contributions to cognitive performance and reduce variability in research findings.