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Articles by I Giegling
Total Records ( 2 ) for I Giegling
  G Donohoe , J Walters , D. W Morris , E. M Quinn , R Judge , N Norton , I Giegling , A. M Hartmann , H. J Moller , P Muglia , H Williams , V Moskvina , R Peel , T O'Donoghue , M. J Owen , M. C O'Donovan , M Gill , D Rujescu and A. Corvin
 

Context  Human and animal studies have implicated the gene NOS1 in both cognition and schizophrenia susceptibility.

Objective  To investigate whether a potential schizophrenia risk single-nucleotide polymorphism (rs6490121) identified in a recent genome-wide association study negatively influences cognition in patients with schizophrenia and healthy control subjects.

Design  A comparison of both cases and controls grouped according to NOS1 genotype (GG vs AG vs AA) on selected measures of cognition in 2 independent samples. We tested for association between NOS1 rs6490121 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attentional control) in an Irish sample. We then sought to replicate the significant results in a German sample.

Setting  Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy volunteers from the general population were ascertained.

Participants  Patients with DSM-IV–diagnosed schizophrenia and healthy control subjects from independent samples of Irish (cases, n = 349; controls, n = 230) and German (cases, n = 232; controls, n = 1344) nationality.

Results  A main effect of NOS1 genotype on verbal IQ and working memory was observed in the Irish sample where the homozygous carriers of the schizophrenia risk G allele performed poorly compared with the other genotype groups. These findings were replicated in the German sample, again with the GG genotype carriers performing below other genotype groups. Post hoc analysis of additional IQ measures (full-scale and performance IQ) in the German sample revealed that NOS1 GG carriers underperformed on these measures also.

Conclusions  NOS1 is associated with clinically significant variation in cognition. Whether this is a mechanism by which schizophrenia risk is increased (eg, via an influence on cognitive reserve) is yet to be confirmed.

  K. K Nicodemus , A. J Law , E Radulescu , A Luna , B Kolachana , R Vakkalanka , D Rujescu , I Giegling , R. E Straub , K McGee , B Gold , M Dean , P Muglia , J. H Callicott , H. Y Tan and D. R. Weinberger
 

Context  NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis.

Objective  To examine epistasis between NRG1 and selected N-methyl-d-aspartate–glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP.

Design  Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls.

Participants  A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172).

Main Outcome Measures  Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level–dependent physiological response during working memory measured by functional magnetic resonance imaging.

Results  We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 x ERBB4 interaction modulates downstream AKT1 signaling.

Conclusion  Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.

 
 
 
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