DNA base excision repair gene polymorphisms modulate human cognitive performance and decline during normal life span

To test the hypothesis that single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with cognitive performance during normal aging, the relationship between SNPs in selected exons in DNA base excision repair (BER) genes and cognitive performance was examined in 712 healthy Norwegian individuals aged 20–75 years. SNPs examined included PolBPro242Arg, hOGG1Ser326Cys, MutYH Met22Val, MutYHHis324Gln, APE1Gln51His, APE1Glu148Asp, XRCC1Lys298Asn, XRCC1Arg7Leu, NEIL1Asp252Asn, and NEIL2Arg257Leu. XRCC1Arg7Leu and PolBPro242Arg were characterized by single nucleotide variations (≤0.1% homozygote SNPs). hOGG1Ser326Cys (Ser/Cys 40.8%/Cys/Cys 5.7%), MutYHHis324Gln (His/Gln37%/Gln/Gln 6.0%) and APE1Glu148Asp (Glu/Asp 51.3%/Asp/Asp 23.0%) were characterized by higher SNP frequencies. MutYHMet22Val, APE1Gln51His and NEIL2Arg257Leu occurred at intermediate SNP frequencies of 11.5, 7.6 and 5.3%, respectively. Interestingly, hOGG1Ser326Cys and APE1Gln51His had genotype by age interactions with general cognitive function, reasoning, control and speed of processing in cross-sectional analysis and a significant effect on longitudinal decline. Dispersed association effects involving MutYHHis324Gln, MutYHMet22Val, PolBPro242Arg and NEIL2Arg257Leu were also detected when APOE or CHRNA4, were included in the statistical model, a result consistent with proposed involvement of the latter markers in human cognitive decline and/or function. In summary, the results support the notion that polymorphisms in BER genes modulate cognitive performance in healthy elderly individuals.

► hOGG1Ser326Cys and APE1Gln51His showed associations with general cognitive function, reasoning, cognitive control and speed of processing, with genotype by age interactions in the cross-sectional analysis and a main effect on longitudinal decline.
► Dispersed association effects involving MutYH, PolB, and NEIL2 were also detected when APOE or CHRNA4, which have been proposed to modulate cognitive aging, were included in the statistical model.
► The results support the notion that polymorphisms in BER genes are associated with cognitive performance and decline in normal elderly individuals.