Systems-level analysis of episodic memory performance and neuropsychiatric disease

Abstract

Episodic memory refers to the ability to store and recall place and time related information. The hippocampus is essential to the encoding of new memories via long-term remodelling of neuronal synapses. However, the understanding of the genetic mechanisms of memory formation and how these genes relate to neuropsychiatric disease is incomplete. In this study, I integrate the information from genome-wide expression patterns from the human hippocampus with multiple genome-wide studies to identify hippocampal gene regulatory networks associated with memory and neuropsychiatric disease. I construct gene co-expression networks from human hippocampi, surgically resected from patients with temporal lobe epilepsy and show that some of these networks are conserved in healthy human brain. By integrating hippocampal gene expression with pre-operative memory performance scores I identify networks whose expression is significantly correlated with memory performance. I then show that the same networks are enriched for common genetic variants (SNP – single nucleotide polymorphisms) associated with verbal recall using data from two independent genome wide association studies (GWAS) of memory. In addition, I integrate hippocampal gene co-expression networks with common variants (SNP) and rare de-novo mutations (DNM) relating to neuropsychiatric disease. These analyses identify two candidate networks of genes co-expressed in the adult human hippocampus (M1 and M3) that may underlie variation in healthy human memory and reveal a convergent gene network for neuropsychiatric disease and memory. This information can be used as a starting point for in vitro and in vivo investigations to identify the genes regulating human memory performance in health and disease.Open Acces