Type

Journal Article

Authors

Michael C O'Donovan
Michael J. Owen
James T.R. Walters
George Kirov
Michael Gill
Eric Kelleher
Elaine Kenny
Derek W Morris
Gary Donohoe
Colm McDonald
and 9 others

Subjects

Pharmacology

Topics
cytoskeleton associated protein arc schizophrenia n methyl d aspartate sequencing activity regulated cytoskeleton associated protein voltage gated sodium channels nmdar arc

Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis (2019)

Abstract Background Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. Methods We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. Results While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10–4) and NMDAR (p = 1.7 × 10–5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10–4). Conclusions In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes.
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Full list of authors on original publication

Michael C O'Donovan, Michael J. Owen, James T.R. Walters, George Kirov, Michael Gill, Eric Kelleher, Elaine Kenny, Derek W Morris, Gary Donohoe, Colm McDonald and 9 others

Experts in our system

1
Michael C O'Donovan
Trinity College Dublin
Total Publications: 23
 
2
Michael J. Owen
Trinity College Dublin
Total Publications: 24
 
3
James Walters
Trinity College Dublin
Total Publications: 12
 
4
G Kirov
Trinity College Dublin
Total Publications: 8
 
5
Michael Gill
Trinity College Dublin
Total Publications: 294
 
6
Eric Kelleher
Trinity College Dublin
Total Publications: 6
 
7
Elaine Kenny
Trinity College Dublin
Total Publications: 32
 
8
Derek Morris
Trinity College Dublin
Total Publications: 168
 
9
Gary Donohoe
Trinity College Dublin
Total Publications: 162
 
10
Colm McDonald
National University of Ireland Galway
Total Publications: 51