Neurophysiologic effect of GWAS derived schizophrenia and bipolar risk variants

Abstract

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) as disease associated variants for schizophrenia (SCZ), bipolar disorder (BPD), or both. Although these results are statistically robust, the functional effects of these variants and their role in the pathophysiology of SCZ or BPD remain unclear. Dissecting the effects of risk genes on distinct domains of brain function can provide important biological insights into the mechanisms by which these genes may confer illness risk. This study used quantitative event related potentials to characterize the neurophysiological effects of well-documented GWAS-derived SCZ/BPD susceptibility variants in order to map gene effects onto important domains of brain function. We genotyped 199 patients with DSM-IV diagnoses of SCZ or BPD and 74 healthy control subjects for 19 risk SNPs derived from previous GWAS findings and tested their association with five neurophysiologic traits (P3 amplitude, P3 latency, N1 amplitude, P2 amplitude, and P50 sensory gating responses) known to be abnormal in psychosis. The TCF4 SNP rs17512836 risk allele showed a significant association with reduced auditory P3 amplitude (P =0.00016) after correction for multiple testing. The same allele was also associated with delayed P3 latency (P =0.005). Our results suggest that a SCZ risk variant in TCF4 is associated with neurophysiologic traits thought to index attention and working memory abnormalities in psychotic disorders. These findings suggest a mechanism by which TCF4 may contribute to the neurobiological basis of psychotic illness.

Altered apolipoprotein C expression in association with cognition impairments and hippocampus volume in schizophrenia and bipolar disorder

“…Intriguingly, our results are consistent with recent genome-wide association studies revealing partial, but not complete, overlap of the genetic risk profiles for BD and SZ (Hall et al, 2014). Our results suggest that the detection of molecular patterns in association with cognitive performance.…”

Electrophysiological Endophenotypes for Schizophrenia

“…187 Another study investigated 19 risk SNPs associated with schizophrenia and did not find an effect for ZNF804A , but found that the TCF4 SNP rs17512836 allele was associated with significant reduction in P300 amplitude and delayed P300 latency. 189 One large pedigree study of a family with a (1;11)(q42;q14.3) translocation, which is associated with major psychiatric disorders including schizophrenia, found that translocation in the DISC1 gene was associated with reduced P300 amplitudes, regardless of psychiatric symptomatology 190 , an effect which was not observed in the former two studies.…”

A new approach to detect epistasis utilizing parallel implementation of ant colony optimization by MapReduce framework

“…Genetic association analysis, which aims at identifying susceptible genetic variations or gene-gene interactions that contribute to the common complex human diseases risk, is attracting more and more attention in recent years [6,7]. Although remarkable achievements have been gained in mapping genetic variants to Mendelian traits, such as cystic fibrosis, the genetic principle and mechanism of many common complex, multifactorial (non-Mendelian) diseases remain mysterious [8].…”