Evaluation of polygenic risk scores for 17 cancer types in relation to cognitive decline in the UK Biobank

Abstract

AbstractBackgroundAccumulating evidence suggests that cancer and dementia are inversely associated, wherein cancer survivors have a roughly 40% reduced dementia incidence and vice versa. Survival and diagnostic bias cannot seemingly account for the relationship fully, but causal explanations have not been adequately investigated. We thus considered a possible inverse shared genetic basis in a large population‐based cohort with extensive individual‐level genotypic and phenotypic data.MethodsThe study population included European ancestry individuals from the UK Biobank who 1) were age 60 or over at baseline assessment (incident dementia analyses; n=190,230 individuals, including 1,887 dementia diagnoses after baseline), or 2) had completed at least one test of fluid intelligence – the capacity to solve problems that require logic and reasoning ability, independent of acquired knowledge – at age 60 or over (fluid intelligence analyses; n=127,529 individuals with 163,266 total measures). We selected known independent genetic risk variants to construct polygenic risk scores (PRS) for cancer overall and each of 17 cancer types. We used multivariable logistic regression and random intercept linear mixed models to evaluate per standard deviation increases of each PRS with respect to dementia status and fluid intelligence, respectively. Bonferroni corrected p‐values were used to evaluate statistical significance.ResultsNone of the cancer PRS were significantly associated with dementia (p>0.05/17=0.0029). The directionality of the overall cancer PRS (856 variants) was consistent with improved cognitive outcomes (p dementia=0.20; p fluid intelligence=0.052). Among PRS for individual cancers, only that for lung cancer (113 variants) was significantly positively associated with fluid intelligence (p=5.9x10‐4). Among variants comprising the various cancer PRS, four independent variants in the human leukocyte antigen (HLA) complex were significantly positively associated with fluid intelligence (p<0.05/856=5.84x10‐5). All were expression quantitative trait loci for major histocompatibility complex class I genes.ConclusionsA PRS for lung cancer was positively associated with fluid intelligence (i.e., decreasing cognitive decline). The association pattern with HLA‐related variants, which code for proteins involved in antigen presentation to stimulate immune response, suggests potential relevance of immune surveillance for the inverse association between dementia and cancer. Further teasing apart their genetic similarities and differences has the potential to clarify mechanisms of dementia pathogenesis.