title: A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.
abstract: Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.
authors: Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
authors: Leonhard
authors: L
authors: Lennertz
authors: Michael
authors: M
authors: Wagner
authors: Wolfgang
authors: W
authors: Wölwer
authors: Anna
authors: A
authors: Schuhmacher
authors: Ingo
authors: I
authors: Frommann
authors: Julia
authors: J
authors: Berning
authors: Svenja
authors: S
authors: Schulze-Rauschenbach
authors: Martin W
authors: MW
authors: Landsberg
authors: Anja
authors: A
authors: Steinbrecher
authors: Michael
authors: M
authors: Alexander
authors: Petra E
authors: PE
authors: Franke
authors: Ralf
authors: R
authors: Pukrop
authors: Stephan
authors: S
authors: Ruhrmann
authors: Andreas
authors: A
authors: Bechdolf
authors: Wolfgang
authors: W
authors: Gaebel
authors: Joachim
authors: J
authors: Klosterkötter
authors: Heinz
authors: H
authors: Häfner
authors: Wolfgang
authors: W
authors: Maier
authors: Rainald
authors: R
authors: Mössner
mesh_terms: D000161:Acoustic Stimulation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000209:etiology* / Q000235:genetics*; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D009483:Neuropsychological Tests; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000150:complications* / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000150:complications* / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; C120531:Shank1 protein, rat