Identification of 13 independent genetic loci associated with cognitive resilience in healthy aging 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. Here we employed a proxy phenotype approach to create a longitudinal cognitive resilience phenotype using past education years and current processing speed, reflecting an average time span of 40 years, in 330,097 individuals from the UK Biobank. A genome-wide association study identified 13 independent genome-wide significant loci that implicate 33 genes. A portion of the resilience genetic signal is distinct from the genetics of intelligence. Functional analyses showed enrichment in several brain regions and involvement of specific cell types, including GABAergic neurons (P=6.59x10-8) and glutamatergic neurons (P=6.98x10-6) in the cortex. Gene-set analyses implicated the biological process - neuron differentiation (P=9.7x10-7) and the cellular component - synaptic part (P=2.14x10-6). Mendelian randomization analysis showed a causative effect of white matter volume on cognitive resilience. These results enhance neurobiological understanding of resilience.