Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia.

Abstract:

:Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ~1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10(-4)), excitability (P=9.0 × 10(-4)) and cell adhesion and trans-synaptic signaling (P=2.4 × 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Lips ES,Cornelisse LN,Toonen RF,Min JL,Hultman CM,International Schizophrenia Consortium.,Holmans PA,O'Donovan MC,Purcell SM,Smit AB,Verhage M,Sullivan PF,Visscher PM,Posthuma D

doi

10.1038/mp.2011.117

subject

Has Abstract

pub_date

2012-10-01 00:00:00

pages

996-1006

issue

10

eissn

1359-4184

issn

1476-5578

pii

mp2011117

journal_volume

17

pub_type

杂志文章
  • The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.

    abstract::Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2009.58

    authors: Ghiani CA,Starcevic M,Rodriguez-Fernandez IA,Nazarian R,Cheli VT,Chan LN,Malvar JS,de Vellis J,Sabatti C,Dell'Angelica EC

    更新日期:2010-02-01 00:00:00

  • Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.

    abstract::Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2017.156

    authors: Greene C,Kealy J,Humphries MM,Gong Y,Hou J,Hudson N,Cassidy LM,Martiniano R,Shashi V,Hooper SR,Grant GA,Kenna PF,Norris K,Callaghan CK,Islam MD,O'Mara SM,Najda Z,Campbell SG,Pachter JS,Thomas J,Williams NM,Humph

    更新日期:2018-11-01 00:00:00

  • Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma.

    abstract::Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells. Initial evidence suggested that sperm RNA is causally linked to the transmission of symptoms induced by traumatic experiences. Here, we...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-018-0271-6

    authors: Gapp K,van Steenwyk G,Germain PL,Matsushima W,Rudolph KLM,Manuella F,Roszkowski M,Vernaz G,Ghosh T,Pelczar P,Mansuy IM,Miska EA

    更新日期:2020-09-01 00:00:00

  • Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes.

    abstract::Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report, we use novel statistica...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2011.108

    authors: Andreasen NC,Wilcox MA,Ho BC,Epping E,Ziebell S,Zeien E,Weiss B,Wassink T

    更新日期:2012-11-01 00:00:00

  • Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study.

    abstract::Familial and twin studies have suggested that anorexia nervosa (AN) is a multifactorial disorder with a substantial genetic contribution. The hSKCa3 potassium channel gene, which contains polymorphic CAG repeats in the coding region and is involved in the regulation of neuronal activity, may be a candidate gene for AN...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4000931

    authors: Koronyo-Hamaoui M,Danziger Y,Frisch A,Stein D,Leor S,Laufer N,Carel C,Fennig S,Minoumi M,Apter A,Goldman B,Barkai G,Weizman A,Gak E

    更新日期:2002-01-01 00:00:00

  • Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder.

    abstract::Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of t...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-019-0420-6

    authors: Bedford SA,Park MTM,Devenyi GA,Tullo S,Germann J,Patel R,Anagnostou E,Baron-Cohen S,Bullmore ET,Chura LR,Craig MC,Ecker C,Floris DL,Holt RJ,Lenroot R,Lerch JP,Lombardo MV,Murphy DGM,Raznahan A,Ruigrok ANV,Smith E

    更新日期:2020-03-01 00:00:00

  • A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

    abstract::Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger se...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2012.57

    authors: Revel FG,Moreau JL,Pouzet B,Mory R,Bradaia A,Buchy D,Metzler V,Chaboz S,Groebke Zbinden K,Galley G,Norcross RD,Tuerck D,Bruns A,Morairty SR,Kilduff TS,Wallace TL,Risterucci C,Wettstein JG,Hoener MC

    更新日期:2013-05-01 00:00:00

  • Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease.

    abstract::The role of innate immunity and microglia in the brain is currently a matter of great debate and controversy. While several studies have provided evidence that they contribute to neurodegeneration in various animal models of brain diseases and traumas, others have shown that their inhibition may in contrast be associa...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/sj.mp.4001809

    authors: Simard AR,Rivest S

    更新日期:2006-04-01 00:00:00

  • Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function.

    abstract::Corticotropin-releasing hormone (CRH) is the principal regulator of the hypothalamic-pituitary-adrenal (HPA) axis and an activator of the sympathoadrenal (SA) and systemic sympathetic (SS) systems. Mental disorders, including major depression and, more recently, Alzheimer's disease have been associated with dysregulat...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4000720

    authors: Willenberg HS,Bornstein SR,Hiroi N,Päth G,Goretzki PE,Scherbaum WA,Chrousos GP

    更新日期:2000-03-01 00:00:00

  • Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.

    abstract::Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signali...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2016.160

    authors: Brooker SM,Gobeske KT,Chen J,Peng CY,Kessler JA

    更新日期:2017-06-01 00:00:00

  • Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder.

    abstract::Gamma-aminobutyric acid (GABA(A)) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABA(A) receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes o...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4002054

    authors: Geuze E,van Berckel BN,Lammertsma AA,Boellaard R,de Kloet CS,Vermetten E,Westenberg HG

    更新日期:2008-01-01 00:00:00

  • Oligodendrocyte lineage cells and depression.

    abstract::Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a consensus about its pathogenesis. There are data to support several different theories of causation, including the mono...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/s41380-020-00930-0

    authors: Zhou B,Zhu Z,Ransom BR,Tong X

    更新日期:2021-01-01 00:00:00

  • Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features.

    abstract::The 'neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2015.192

    authors: Heidari M,Johnstone DM,Bassett B,Graham RM,Chua AC,House MJ,Collingwood JF,Bettencourt C,Houlden H,Ryten M,Olynyk JK,Trinder D,Milward EA

    更新日期:2016-11-01 00:00:00

  • The role of the retinoids in schizophrenia: genomic and clinical perspectives.

    abstract::Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processe...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/s41380-019-0566-2

    authors: Reay WR,Cairns MJ

    更新日期:2020-04-01 00:00:00

  • Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model.

    abstract::Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN-/-) mice developed Alzheimer's like pathologies, cerebral insulin resistance, and cogniti...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-020-0701-0

    authors: Ng RC,Jian M,Ma OK,Bunting M,Kwan JS,Zhou GJ,Senthilkumar K,Iyaswamy A,Chan PK,Li M,Leung KM,Kumar Durairajan SS,Lam KS,Chu LW,Festenstein R,Chung SK,Chan KH

    更新日期:2020-03-04 00:00:00

  • Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population.

    abstract::Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few s...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2015.12

    authors: Clarke TK,Lupton MK,Fernandez-Pujals AM,Starr J,Davies G,Cox S,Pattie A,Liewald DC,Hall LS,MacIntyre DJ,Smith BH,Hocking LJ,Padmanabhan S,Thomson PA,Hayward C,Hansell NK,Montgomery GW,Medland SE,Martin NG,Wright MJ

    更新日期:2016-03-01 00:00:00

  • Treatment-resistant anxiety disorders.

    abstract::Several epidemiological studies confirmed that Anxiety Disorders as a group are the most prevalent psychiatric conditions in the United States. The importance of these conditions is underlined by the fact that they cause significant disability, poor quality of life, alcohol and drug abuse. Anxiety disorders are treata...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/sj.mp.4001852

    authors: Bystritsky A

    更新日期:2006-09-01 00:00:00

  • Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.

    abstract::Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions a...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,多中心研究

    doi:10.1038/mp.2013.42

    authors: Hodge JC,Mitchell E,Pillalamarri V,Toler TL,Bartel F,Kearney HM,Zou YS,Tan WH,Hanscom C,Kirmani S,Hanson RR,Skinner SA,Rogers RC,Everman DB,Boyd E,Tapp C,Mullegama SV,Keelean-Fuller D,Powell CM,Elsea SH,Morton CC

    更新日期:2014-03-01 00:00:00

  • Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals.

    abstract::Although therapeutic interventions in attention-deficit/hyperactivity disorder (ADHD) still focus on the dopaminergic system, recent studies indicate a serotonergic dysfunction in this disease as well. In that respect, several variants of the tryptophan hydroxylase gene (TPH2), which codes for the rate-limiting enzyme...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2008.39

    authors: Baehne CG,Ehlis AC,Plichta MM,Conzelmann A,Pauli P,Jacob C,Gutknecht L,Lesch KP,Fallgatter AJ

    更新日期:2009-11-01 00:00:00

  • Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia.

    abstract::Several studies suggest that decreased expression of presynaptic proteins may be characteristic of schizophrenia. We examined one such protein, synapsin, in schizophrenia and bipolar disorder. Samples of hippocampal tissue from controls (n = 13), patients with schizophrenia (n = 16), or bipolar disorder (n = 6), and s...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4001158

    authors: Vawter MP,Thatcher L,Usen N,Hyde TM,Kleinman JE,Freed WJ

    更新日期:2002-01-01 00:00:00

  • A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

    abstract::Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started wi...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2010.6

    authors: Arcos-Burgos M,Jain M,Acosta MT,Shively S,Stanescu H,Wallis D,Domené S,Vélez JI,Karkera JD,Balog J,Berg K,Kleta R,Gahl WA,Roessler E,Long R,Lie J,Pineda D,Londoño AC,Palacio JD,Arbelaez A,Lopera F,Elia J,Hakon

    更新日期:2010-11-01 00:00:00

  • Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow.

    abstract::The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V(158)M COMT genotype was obtained ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4001616

    authors: Ho BC,Wassink TH,O'Leary DS,Sheffield VC,Andreasen NC

    更新日期:2005-03-01 00:00:00

  • Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials.

    abstract::We searched Embase, PubMed, and CENTRAL from inception until 22 May 2020 to investigate which antipsychotics and/or mood stabilizers are better for patients with bipolar disorder in the maintenance phase. We performed two categorical network meta-analyses. The first included monotherapy studies and studies in which th...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-020-00946-6

    authors: Kishi T,Ikuta T,Matsuda Y,Sakuma K,Okuya M,Mishima K,Iwata N

    更新日期:2020-11-11 00:00:00

  • Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D(2) receptor gene.

    abstract::A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional po...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/sj.mp.4001422

    authors: Kishida I,Kawanishi C,Furuno T,Kato D,Ishigami T,Kosaka K

    更新日期:2004-03-01 00:00:00

  • Constitutional mechanisms of vulnerability and resilience to nicotine dependence.

    abstract::The core nature of nicotine dependence is evident in wide variations in how individuals become and remain smokers. Individuals with pre-existing behavioral traits are more likely to develop nicotine dependence and experience difficulty when attempting to quit. Many molecular factors likely contribute to individual var...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章,评审

    doi:10.1038/mp.2009.16

    authors: Hiroi N,Scott D

    更新日期:2009-07-01 00:00:00

  • Impact of video games on plasticity of the hippocampus.

    abstract::The hippocampus is critical to healthy cognition, yet results in the current study show that action video game players have reduced grey matter within the hippocampus. A subsequent randomised longitudinal training experiment demonstrated that first-person shooting games reduce grey matter within the hippocampus in par...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2017.155

    authors: West GL,Konishi K,Diarra M,Benady-Chorney J,Drisdelle BL,Dahmani L,Sodums DJ,Lepore F,Jolicoeur P,Bohbot VD

    更新日期:2018-07-01 00:00:00

  • Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits.

    abstract::The methionine-folate cycle-dependent one-carbon metabolism is implicated in the pathophysiology of schizophrenia. Since schizophrenia is a developmental disorder, we examined the effects that perturbation of the one-carbon metabolism during gestation has on mice progeny. Pregnant mice were administered methionine equ...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2017.164

    authors: Alachkar A,Wang L,Yoshimura R,Hamzeh AR,Wang Z,Sanathara N,Lee SM,Xu X,Abbott GW,Civelli O

    更新日期:2018-02-01 00:00:00

  • The development of Kraepelin's mature diagnostic concept of hebephrenia: a close reading of relevant texts of Hecker, Daraszkiewicz, and Kraepelin.

    abstract::In developing his mature concept of hebephrenic dementia praecox (DP) in his 4th (1893) through 6th textbook editions (1899), Kraepelin worked from the hebephrenic syndrome first described by Hecker (1871) and then carefully studied by his student Daraszkiewicz (1892). Working under Kraepelin's supervision, Daraszkiew...

    journal_title:Molecular psychiatry

    pub_type: 历史文章,杂志文章,评审

    doi:10.1038/s41380-019-0411-7

    authors: Kendler KS

    更新日期:2020-01-01 00:00:00

  • White matter microstructural alterations across four major psychiatric disorders: mega-analysis study in 2937 individuals.

    abstract::Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophr...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/s41380-019-0553-7

    authors: Koshiyama D,Fukunaga M,Okada N,Morita K,Nemoto K,Usui K,Yamamori H,Yasuda Y,Fujimoto M,Kudo N,Azechi H,Watanabe Y,Hashimoto N,Narita H,Kusumi I,Ohi K,Shimada T,Kataoka Y,Yamamoto M,Ozaki N,Okada G,Okamoto Y,Ha

    更新日期:2020-04-01 00:00:00

  • The joint impact of cognitive performance in adolescence and familial cognitive aptitude on risk for major psychiatric disorders: a delineation of four potential pathways to illness.

    abstract::How do joint measures of premorbid cognitive ability and familial cognitive aptitude (FCA) reflect risk for a diversity of psychiatric and substance use disorders? To address this question, we examined, using Cox models, the predictive effects of school achievement (SA) measured at age 16 and FCA-assessed from SA in s...

    journal_title:Molecular psychiatry

    pub_type: 杂志文章

    doi:10.1038/mp.2017.78

    authors: Kendler KS,Ohlsson H,Keefe RSE,Sundquist K,Sundquist J

    更新日期:2018-04-01 00:00:00