Details

Autor(en) / Beteiligte

• Rees, Elliott
• Carrera, Noa
• Morgan, Joanne
• Hambridge, Kirsty
• Escott-Price, Valentina
• Pocklington, Andrew J.
• Richards, Alexander L.
• Pardiñas, Antonio F.
• Alizadeh, Behrooz Z.
• van Amelsvoort, Therese
• Bartels-Velthuis, Agna A.
• van Beveren, Nico J.
• Bruggeman, Richard
• Cahn, Wiepke
• de Haan, Lieuwe
• Delespaul, Philippe
• Meijer, Carin J.
• Myin-Germeys, Inez
• Kahn, Rene S.
• Schirmbeck, Frederike
• Simons, Claudia J.P.
• van Haren, Neeltje E.
• van Os, Jim
• van Winkel, Ruud
• Luykx, Jurjen J.
• McDonald, Colm
• Donohoe, Gary
• Morris, Derek W.
• Kenny, Elaine
• Kelleher, Eric
• Gill, Michael
• Corvin, Aiden
• Kirov, George
• Walters, James T.R.
• Holmans, Peter
• Owen, Michael J.
• O’Donovan, Michael C.

Titel

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

Ist Teil von

• Biological psychiatry (1969), 2019-04, Vol.85 (7), p.554-562

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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). 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.