Thirteen Independent Genetic Loci Associated with Preserved Processing Speed in a Study of Cognitive Resilience in 330,097 Individuals in the UK Biobank

Cognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning and is important for maintaining quality of life while aging. UK Biobank (UKB) does not have direct measurements of the same cognitive phenotype at distal timepoints. Therefore, we used number of education years (EY) as a proxy phenotype for past cognitive performance. Current cognitive performance was determined based on processing speed. This approach captured an average time span of 40 years between past and current cognitive performance in 330,097 individuals. A confounding factor was that EY is highly polygenic and masked the genetics of resilience. To overcome this, we employed Genomics Structural Equation Modelling (GenomicSEM) to perform a GWAS-by-subtraction using two GWAS, one GWAS of EY and resilience and a second GWAS of EY but not resilience. Subtracting one from the other generated a GWAS of Resilience. Replication of this approach was shown using independent discovery and replication samples and the full GWAS results were examined further using functional genomics analysis. We found 13 independent genetic loci for Resilience. Functional analyses showed enrichment in several brain regions and involvement of specific cell types, including GABAergic neurons (P=6.59×10−8) and glutamatergic neurons (P=6.98×10−6) in the cortex. Gene-set analyses implicated the biological process “neuron differentiation” (P=9.7×10−7) and the cellular component “synaptic part” (P=2.14×10−6). Mendelian randomization analysis showed a causative effect of white matter volume on cognitive resilience. These results enhance neurobiological understanding of resilience. Author Summary We all differ in our levels of resilience to cognitive decline as we age. We know that a healthy lifestyle protects us from cognitive decline, however we do not know the role that our genes play in this process. By identifying the genes involved, we can then examine their biology, which could point to therapeutic interventions that may increase our resilience. To study the genetics of cognitive resilience we need large datasets with the same measures of cognitive performance over a long period of time. That data are currently not available, even within large biobanks. Instead, we used a measure of processing speed for current cognitive performance and number of years in education as a proxy measure of past cognitive performance to study genes associated with resistance over time in 330,097 individuals from the UK Biobank. After testing our method to show its replicability, we identified 13 genetic regions containing many genes that were associated with resilience. We showed that these genes function in several brain regions and different cell types. We also showed that white matter volume in the brain affects resilience. This study increases our biological understanding of resilience.