BACKGROUND: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. METHODS: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish case-control samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. RESULTS: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10(-8); odd ratio = .73, 95% confidence interval = .65-.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA. CONCLUSIONS: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain.
BACKGROUND:Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. METHODS: Analysis of genetic association was based on data mining of genotypes from a German genome-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish case-control samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. RESULTS: Allelic associations were found across all three samples for eight common SNPs in the complement control-related gene CSMD2 (CUB and Sushi Multiple Domains 2) on chromosome 1p35.1-34.3, of which rs911213 reached a statistical significance comparable to that of a genome wide threshold (p value = 4.0 × 10(-8); odd ratio = .73, 95% confidence interval = .65-.82). The second most significant gene was CSMD1 on chromosome 8p23.2, a homologue to CSMD2. In addition, we observed replicated associations in the complement surface receptor CD46 as well as the major histocompatibility complex genes HLA-DMB and HLA-DOA. CONCLUSIONS: These data demonstrate a significant role of complement control-related genes in the etiology of schizophrenia and support disease mechanisms that involve the activity of immunity-related pathways in the brain.
Authors: Emily G Severance; Armin Alaedini; Shuojia Yang; Meredith Halling; Kristin L Gressitt; Cassie R Stallings; Andrea E Origoni; Crystal Vaughan; Sunil Khushalani; F Markus Leweke; Faith B Dickerson; Robert H Yolken Journal: Schizophr Res Date: 2012-03-24 Impact factor: 4.939
Authors: Caragh P Stapleton; Andreas Heinzel; Weihua Guan; Peter J van der Most; Jessica van Setten; Graham M Lord; Brendan J Keating; Ajay K Israni; Martin H de Borst; Stephan J L Bakker; Harold Snieder; Michael E Weale; Florence Delaney; Maria P Hernandez-Fuentes; Roman Reindl-Schwaighofer; Rainer Oberbauer; Pamala A Jacobson; Patrick B Mark; Fiona A Chapman; Paul J Phelan; Claire Kennedy; Donal Sexton; Susan Murray; Alan Jardine; Jamie P Traynor; Amy Jayne McKnight; Alexander P Maxwell; Laura J Smyth; William S Oetting; Arthur J Matas; Roslyn B Mannon; David P Schladt; David N Iklé; Gianpiero L Cavalleri; Peter J Conlon Journal: Am J Transplant Date: 2019-03-28 Impact factor: 8.086
Authors: J J Luykx; S C Bakker; E Lentjes; M Neeleman; E Strengman; L Mentink; J DeYoung; S de Jong; J H Sul; E Eskin; K van Eijk; J van Setten; J E Buizer-Voskamp; R M Cantor; A Lu; M van Amerongen; E P A van Dongen; P Keijzers; T Kappen; P Borgdorff; P Bruins; E M Derks; R S Kahn; R A Ophoff Journal: Mol Psychiatry Date: 2013-01-15 Impact factor: 15.992
Authors: Emily G Severance; Kristin L Gressitt; Meredith Halling; Cassie R Stallings; Andrea E Origoni; Crystal Vaughan; Sunil Khushalani; Armin Alaedini; Didier Dupont; Faith B Dickerson; Robert H Yolken Journal: Neurobiol Dis Date: 2012-07-16 Impact factor: 5.996
Authors: H Yu; H Yan; J Li; Z Li; X Zhang; Y Ma; L Mei; C Liu; L Cai; Q Wang; F Zhang; N Iwata; M Ikeda; L Wang; T Lu; M Li; H Xu; X Wu; B Liu; J Yang; K Li; L Lv; X Ma; C Wang; L Li; F Yang; T Jiang; Y Shi; T Li; D Zhang; W Yue Journal: Mol Psychiatry Date: 2016-12-06 Impact factor: 15.992
Authors: Shashwath A Meda; Gualberto Ruaño; Andreas Windemuth; Kasey O'Neil; Clifton Berwise; Sabra M Dunn; Leah E Boccaccio; Balaji Narayanan; Mohan Kocherla; Emma Sprooten; Matcheri S Keshavan; Carol A Tamminga; John A Sweeney; Brett A Clementz; Vince D Calhoun; Godfrey D Pearlson Journal: Proc Natl Acad Sci U S A Date: 2014-04-28 Impact factor: 11.205
Authors: Ken H Loh; Philipp S Stawski; Austin S Draycott; Namrata D Udeshi; Emily K Lehrman; Daniel K Wilton; Tanya Svinkina; Thomas J Deerinck; Mark H Ellisman; Beth Stevens; Steven A Carr; Alice Y Ting Journal: Cell Date: 2016-08-25 Impact factor: 41.582