Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

Abstract

Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder, and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes- processing speed, whole-brain white matter fractional anisotropy, and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of <0.05 with all three phenotypes in the expected direction: decreased processing speed, decreased fractional anisotropy, and increased risk of schizophrenia spectrum disorder. A single SNP, rs8234, in the 3′ untranslated region (UTR) of voltage-gated potassium channel subfamily Q member 1 (KCNQ1) was identified. Rs8234 has been shown to affect KCNQ1 expression levels, and KCNQ1 levels have been shown to affect neuronal action potentials. This exploratory analysis provides preliminary data suggesting that KCNQ1 may contribute to the shared risk for diminished processing speed, diminished white mater integrity, and increased risk of schizophrenia.

Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children

“…These are widely distributed in all brain areas and play an important role in neuronal excitability. Data was provided suggesting that potassium channel gene KCNQ1 may contribute to the shared risk for diminished processing speed and white mater integrity ( Bruce et al, 2017 ).…”

Persistence: Using Protein Turnover to Expand the Applications of Transcriptomics

“…Multiple studies in animals, iPSCs, and humans have noted increased potassium and sodium channel expression and activity in the prefrontal cortex. These changes were associated with abnormal neuronal activity, diminished synaptic plasticity, and impaired white matter integrity, all of which are characteristic of SCZ [17][18][19][20][21][22]. Additionally, antipsychotics can reverse these ion channel alterations, suggesting that this is a key mechanism in SCZ pathology [23][24][25].…”

“…These results are encouraging that persistence is a meaningful measure because these pathways have been implicated in SCZ in prior studies. For example, ion homeostasis was the most commonly altered category in our high persistent pathways [17][18][19][20][21][22].…”

Neurogenomics – towards a more rigorous science

“…Candidate gene association studies with imaging phenotypes continue to be carried out with all of the methodological problems referred to above. Clearly they are still being positively reviewed, both for funding applications and for publication, as they continue to appear in the literature on a regular basis, including these examples just from the last several months: (Bruce et al ., ; Dalvie et al ., ; Gonzalez et al ., ; Jasinska et al ., ; Lubeiro et al ., ; Mallas et al ., ; Swartz et al ., ). This is despite the very solid empirical finding that most, perhaps all, such reported results will not generalise beyond the sample studied.…”