Brain structure and cognition are associated with variability in DNA repair genes
Poster No:
92
Submission Type:
Abstract Submission
Authors:
Nicolas Cherbuin1, Hardip Patel2, Erin Walsh3, Ananthan Ambikairajah4, Richard Burns2, Anne Brüstle2, Lene Juel Rasmussen5
Institutions:
1The Australian National University, Canberra, ACT, 2Australian National University, Canberra, ACT, 3Australian National University, Canberra, AL, 4University of Canberra, Canberra, ACT, 5University of Copenhagen, Copenhagen, Zealand
First Author:
Co-Author(s):
Introduction:
Inflammation and oxidative stress are known to contribute to neurodegeneration and are increasingly being identified as mediating the effects of environmental and lifestyle risk factors for dementia [1,2]. DNA damage associated with oxidative stress is likely to contribute to these effects. However, the extent to which genetic variability in DNA repair is a major moderator of neurodegeneration is unclear. This study aims to address this question by testing associations between single nucleotide polymorphism (SNP) of base excision pair repair genes, cognitive function and brain structure.
Methods:
Community-living participants (n=488,159; 56.54 years (8.09); 54.2% female) taking part in the UK biobank study for whom cognitive and genetic measures were available were included. In addition, 39,060 participants for whom neuroimaging measures were also available contributed to the genetic-brain analyses. SNPs tested included OGG1 (rs1052133, rs104893751), NEIL1 (rs7402844, rs5745906), NEIL2 (rs6601606), NEIL3 (rs10013040, rs13112390, rs13112358, rs1395479), MUTYH (rs34612342, rs200165598, rs77542170, rs200844166, rs200495564), NTHL1 (rs150766139, rs2516739). Cognitive outcome measures included fluid intelligence (FIQ), symbol-digit matching task (SDMT), visual matching (MATCH), and trail making (TRAIL). MRI scan were acquired on 3T Siemens Skyra using a 32-channel head coil with a T1-weighted 3D magnetization-prepared rapid acquisition gradient echo sequence (sagittal orientation; 1 × 1 × 1 mm; FOV = 208 × 256 × 256) and segmented with Freesurfer (version 6.0.5). A priori selected ROIs included total brain (TBV), grey matter (GMV), white matter (WMV), white matter hyperintensities (WMH), as well as left and right hippocampi (LHC/RHC) volumes. Hierarchical regression analyses were used to test the associations between SNPs and cognitive or brain outcomes after controlling for covariates. In a second step, significant SNPs were combined into a genetic risk index ranging from 0 (no risk) to 10 (greatest risk), and further regression analyses were conducted to test its associations with cognitive and brain outcomes. α was set at < 0.05, Bonferroni corrected.
Results:
Several significant associations between base excision repair SNPs and cognitive outcomes were identified. Strongest associations accounted for 1-6% difference in cognitive function and were detected for OGG1 (rs1052133HTZ-MATCH: β 2.22, p=0.003, rs104893751HMZ-MATCH: β -5.73, p=0.002), NEIL1 (rs7402844HTZ-MATCH: β -11.27, p<0.001), NEIL2 (rs6601606HMZ-FIQ: β -1.46, p<0.00001; rs6601606HMZ-MATCH: β -11.27, p=0.0002), NEIL3 (rs10013040HTZ-SDMT: β 0.085, p<0.004; rs10013040HTZ-MATCH: β -1.03, p<0.003; rs13112390HTZ-FIQ: β 0.080, p=0.007; rs13112390HTZ-MATCH: β -3,53, p<0.0001; rs13112358HTZ-FIQ: β 0.078, p=0.003; rs13112358HTZ-MATCH: β -2.88, p=0.0001), MUTYH (rs200495564HTZ-TRAIL: β 21.29, p=0.0003; rs2516739HTZ-TRAIL: β 6.09, p<0.001). Significant associations were also detected with brain volumes for NEIL3 (rs13112390HTZ-GM: β -3008, p<0.009; rs13112358HTZ-GM: β 1,914, p<0.022), and with the genetic risk index for most ROIs. Associations varied by age and sex with stronger effects detected in middle-age women (see Figure 1).
·Figure 1. Age and sex interactions between genetic risk index and hippocampal volumes.
Conclusions:
Variation in a number of base pair repair genes was associated with older adults' cognitive function and brain structure. For cognition, effects were stronger in middle-aged women, while for brain volumes associations were stronger in older participants with some opposite effects in men and women. Given the role played by DNA repair genes in resolving damage caused by oxidative stress/inflammation, their possible contribution to dementia, other related conditions, and their risk factors, needs further investigation.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Genetics:
Genetic Association Studies 2
Higher Cognitive Functions:
Executive Function, Cognitive Control and Decision Making
Lifespan Development:
Aging
Modeling and Analysis Methods:
Segmentation and Parcellation
Keywords:
Aging
Cognition
Data analysis
MRI
Other - genetics; DNA repair
1|2Indicates the priority used for review
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2. Cherbuin, N., Walsh, E., Baune, B., Anstey, K. (2019). Oxidative stress, inflammation and risk of neurodegeneration in a population sample. European Journal of Neurology, 26(11):1347-1354. doi: 10.1111/ene.13985