Implication of the APP Gene in Intellectual Abilities

Abstract

Background: Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC) plays an essential role. Objectives: To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation. Methods: The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N=5,165). As Alzheimer's disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls). Results: The ARC complex revealed association with verbal and total IQ (empirical p=0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p=0.018), within the APP gene, was confirmed in the AD sample (p=2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2. Discussion: This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD.