Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

Abstract

Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from 4 large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA®). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development ( REST ), oligodendrocyte maturation ( TNFRSF21 ), and myelination ( ARFGEF1 ). IPA® identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions ( MPO , FOXO1 , PDE3A , TSLP , NLRP9 , ADAMTS5 , ROBO1 , REST ). Furthermore, IPA® identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.

Discovery and replication of blood-based proteomic signature of PTSD in 9/11 responders

“…The fifth replicated protein, tumor necrosis factor receptor superfamily member 21 (TNFRSF21), plays a role in neuronal apoptosis and the negative regulation of oligodendrocyte maturation [42]. The TNFRSF21 gene has been found to be differentially expressed in PTSD [43,44], including in postmortem brain samples in orbitofrontal cortex and dorsal anterior cingulate cortex regions [17], and genetic variants within this gene have emerged in genome-wide association studies of panic disorder [45] and depression [46,47]. Finally, DRAXIN a role in neural development and has been implicated in autism spectrum disorder and obsessive-compulsive disorder [48].…”

APOE ε4 in Depression-Associated Memory Impairment—Evidence from Genetic and MicroRNA Analyses

“…A step in this direction has been made by Thalamuthu and colleagues [ 54 ] who investigated the interaction between MDD and genetic variants on different domains of cognition in a GWAS approach. Although their measurements of current MDD and cognition were very heterogeneous and they could not measure APOE ε4 status directly, they were able to identify the amyloid precursor protein network as an important mechanism for executive function in a considerably large sample.…”

Cognitive impairment in psychiatric diseases: Biomarkers of diagnosis, treatment, and prevention

“…In addition to SCZ, a GWAS of MDD and cognitive function found that there were 48, 116, and 32 SNPs significantly associated with executive function domains, processing speed, and global cognition, respectively. Some of these SNPs are located in genes expressed in brain with important roles in neuronal development (REST), oligodendrocyte maturation (TNFRSF21) and myelination (ARFGEF1) ( Thalamuthu et al, 2022 ). A large GWAS combining data on SCZ ( n = 82,315), BD ( n = 51,710), and general intelligence ( n = 269,867) identified 75 distinct genomic loci associated with SCZ and intelligence, and 12 loci associated with BD and intelligence.…”