Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling

Tuomo Mäki-Marttunen, Glenn T. Lines, Andrew G. Edwards, Aslak Tveito, Anders M. Dale, Gaute T. Einevoll, Ole A. Andreassen

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na+ channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.

Original languageEnglish (US)
Number of pages1
JournalTranslational psychiatry
Volume7
Issue number11
DOIs
StatePublished - Nov 17 2017
Externally publishedYes

Fingerprint

Schizophrenia
Neurons
Sinoatrial Node
Genes
Pyramidal Cells
Comorbidity
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Genome-Wide Association Study
Genomics
Antipsychotic Agents
Action Potentials
Cardiac Arrhythmias
Homeostasis
Calcium

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling. / Mäki-Marttunen, Tuomo; Lines, Glenn T.; Edwards, Andrew G.; Tveito, Aslak; Dale, Anders M.; Einevoll, Gaute T.; Andreassen, Ole A.

In: Translational psychiatry, Vol. 7, No. 11, 17.11.2017.

Research output: Contribution to journalArticle

Mäki-Marttunen, Tuomo ; Lines, Glenn T. ; Edwards, Andrew G. ; Tveito, Aslak ; Dale, Anders M. ; Einevoll, Gaute T. ; Andreassen, Ole A. / Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling. In: Translational psychiatry. 2017 ; Vol. 7, No. 11.
@article{4b771f96e597477d8864bb7e2966158e,
title = "Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling",
abstract = "Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na+ channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.",
author = "Tuomo M{\"a}ki-Marttunen and Lines, {Glenn T.} and Edwards, {Andrew G.} and Aslak Tveito and Dale, {Anders M.} and Einevoll, {Gaute T.} and Andreassen, {Ole A.}",
year = "2017",
month = "11",
day = "17",
doi = "10.1038/s41398-017-0007-4",
language = "English (US)",
volume = "7",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling

AU - Mäki-Marttunen, Tuomo

AU - Lines, Glenn T.

AU - Edwards, Andrew G.

AU - Tveito, Aslak

AU - Dale, Anders M.

AU - Einevoll, Gaute T.

AU - Andreassen, Ole A.

PY - 2017/11/17

Y1 - 2017/11/17

N2 - Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na+ channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.

AB - Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na+ channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.

UR - http://www.scopus.com/inward/record.url?scp=85054726274&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054726274&partnerID=8YFLogxK

U2 - 10.1038/s41398-017-0007-4

DO - 10.1038/s41398-017-0007-4

M3 - Article

C2 - 30446648

AN - SCOPUS:85054726274

VL - 7

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

IS - 11

ER -