Ion channels and schizophrenia: a gene set-based analytic approach to GWAS data for biological hypothesis testing

Abstract

Schizophrenia is a complex genetic disorder. Gene set-based analytic (GSA) methods have been widely applied for exploratory analyses of large, high-throughput datasets, but less commonly employed for biological hypothesis testing. Our primary hypothesis is that variation in ion channel genes contribute to the genetic susceptibility to schizophrenia. We applied Exploratory Visual Analysis (EVA), one GSA application, to analyze European-American (EA) and African-American (AA) schizophrenia genome-wide association study datasets for statistical enrichment of ion channel gene sets, comparing GSA results derived under three SNP-to-gene mapping strategies: (1) GENIC; (2) 500-Kb; (3) 2.5-Mb and three complimentary SNP-to-gene statistical reduction methods: (1) minimum p value (pMIN); (2) a novel method, proportion of SNPs per Gene with p-values below a pre-defined α-threshold (PROP); and (3) the truncated product method (TPM). In the EA analyses, ion channel gene set(s) were enriched under all mapping and statistical approaches. In the AA analysis, ion channel gene set(s) were significantly enriched under pMIN for all mapping strategies and under PROP for broader mapping strategies. Less extensive enrichment in the AA sample may reflect true ethnic differences in susceptibility, sampling or case ascertainment differences, or higher dimensionality relative to sample size of the AA data. More consistent findings under broader mapping strategies may reflect enhanced power due to increased SNP inclusion, enhanced capture of effects over extended haplotypes or significant contributions from regulatory regions. While extensive pMIN findings may reflect gene size bias, the extent and significance of PROP and TPM findings suggest that common variation at ion channel genes may capture some of the heritability of schizophrenia.

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

“…The second subnetwork, sp-DMNS, containing precuneus was disconnected significantly only in the SZ probands, and the corresponding genetic network was enriched with ion transport, voltage-gated regulatory, and intracellular signaling genes, all processes associated with neural transmission, whose dysfunction might lead to abnormal brain function (73,74). Some notable top-ranked genes associated with sp-DMNS2 connectivity, such as DGKH, whose differential effects were shown recently to manifest as a failure to disengage DMN during a verbal fluency task in subjects at high familial risk of BP, were candidates (75).…”

Brugada Syndrome ECG Is Highly Prevalent in Schizophrenia

“…22 Accordingly, genetic studies suggest that the pathobiology of schizophrenia involves various voltage-gated ion channels. [28][29][30] Because these proteins also control cardiac electrophysiology, variants in their encoding genes (KCNH2, CACNA1C) may increase arrhythmia and SCD risk. We did not screen KCNH2 and CACNA1C in the patients with Brugada-ECG, but only SCN5A, because SCN5A is the only gene routinely screened at our institution in BrS patients.…”

Disruption of Dopamine Neuron Activity Pattern Regulation through Selective Expression of a Human KCNN3 Mutation

“…Convergent glutamate, GABA, and acetylcholine neurotransmitter systems, as well as multiple voltage-gated and calcium-activated ion channels coordinately regulate action potential firing in dopamine neurons (Shepard and Bunney, 1988, Nedergaard et al, 1993, Overton and Clark, 1997, Wolfart et al, 2001, Wolfart and Roeper, 2002, Tepper and Lee, 2007). Mutations within several ion channels known to regulate dopamine neuron physiology have been linked to mental illnesses, including schizophrenia and bipolar disorder (Liao and Soong, 2010, Askland et al, 2012), yet little is known about how specific channel mutations impact dopamine neuron activity.…”