Age-Dependent Pleiotropy Between General Cognitive Function and Major Psychiatric Disorders

Abstract

Background: General cognitive function predicts psychiatric illness across the life course. This study examines the role of pleiotropy in explaining the link between cognitive function and psychiatric disorder.

Methods: We used two large genome-wide association study data sets on cognitive function-one from older age, n = 53,949, and one from childhood, n = 12,441. We also used genome-wide association study data on educational attainment, n = 95,427, to examine the validity of its use as a proxy phenotype for cognitive function. Using a new method, linkage disequilibrium regression, we derived genetic correlations, free from the confounding of clinical state between psychiatric illness and cognitive function.

Results: We found a genetic correlation of .711 (p = 2.26e-12) across the life course for general cognitive function. We also showed a positive genetic correlation between autism spectrum disorder and cognitive function in childhood (rg = .360, p = .0009) and for educational attainment (rg = .322, p = 1.37e-5) but not in older age. In schizophrenia, we found a negative genetic correlation between older age cognitive function (rg = -.231, p = 3.81e-12) but not in childhood or for educational attainment. For Alzheimer's disease, we found negative genetic correlations with childhood cognitive function (rg = -.341, p = .001), educational attainment (rg = -.324, p = 1.15e-5), and with older age cognitive function (rg = -.324, p = 1.78e-5).

Conclusions: The pleiotropy exhibited between cognitive function and psychiatric disorders changed across the life course. These age-dependent associations might explain why negative selection has not removed variants causally associated with autism spectrum disorder or schizophrenia.

Keywords: Aging; Autism; Cognitive function; Genetics; Pleiotropy; Schizophrenia.