The contribution of three strong candidate schizophrenia susceptibility genes in demographically distinct populations

Hall, Diana; Gogos, Joseph A.; Karayiorgou, Maria

doi:10.1111/j.1601-183x.2004.00078.x

Cited by 101 publications

(62 citation statements)

References 32 publications

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“…Several studies were excluded because of sample duplication with another study (Yue et al, 2006), lack of sufficient data even after requesting informative data from the authors (Fallin et al, 2005;Goldberg et al, 2006;Hall et al, 2004;Nicodemus et al, 2007). M12, M15, M23 and M24 were excluded for BP because they were analyzed in only one or two studies (Schulze et al, 2005).…”

Section: Description Of Studiesmentioning

confidence: 99%

“…Shortly afterward, the G72/ G30 gene complex (G72 is now officially known as D-aminoacid oxidase activator, DAOA) was associated, independently, with each disorder (Chumakov et al, 2002;Hattori et al, 2003). An association has been reported in multiple independent studies (Addington et al, 2004;Chen et al, 2004;Fallin et al, 2005;Hall et al, 2004;Hong et al, 2006;Korostishevsky et al, 2004;Korostishevsky et al, 2006;Ma et al, 2006;Schulze et al, 2005;Schumacher et al, 2004;Wang et al, 2004;Williams et al, 2006;Yue et al, 2006;Yue et al, 2007;Zou et al, 2005). However, several studies did not find association with traditional BP or SCZ phenotype (Bakker et al, 2007;Goldberg et al, 2006;Liu et al, 2006;Mulle et al, 2005;Vilella et al, 2007;Wood et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

Shi

Badner

Gershon

et al. 2008

Schizophrenia Research

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The G72/G30 gene complex (G72 also known as D-amino acid oxidase activator, DAOA) and its chromosomal region 13q32-34 have been linked and associated with both schizophrenia (SCZ) and bipolar disorder (BP) in multiple studies, including our initial association report on BP. However, the inconsistency of associated variants across studies is obvious. Previous meta-analyses had small data sets. The present meta-analysis combined 18 association articles published before April of 2007. There were 19 independent studies of SCZ, with 4304 cases, 5423 controls, and 1384 families, and four independent studies of BP with 1145 cases, 1829 controls, and 174 families. Of 15 single nucleotide polymorphisms (SNPs) analyzed in the 95-kb G72/G30 gene region, M18/rs947267 and M22/rs778293 showed association with SCZ in Asians, and M24/rs1421292 with SCZ in Europeans. The associations of C allele at M18 and A allele at M22 with SCZ in Asians survived conservative Bonferroni correction for multiple testing for 15 markers and subgroup analysis (adjusted P = 0.0000253 for M18; adjusted P = 0.009 for M22). No single maker showed evidence of overall association with BP. These results suggest that G72/G30 may influence susceptibility to schizophrenia with weak effects.

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Section: Description Of Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

Shi

Badner

Gershon

et al. 2008

Schizophrenia Research

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“…This HapB IRE includes one of the Hap ICE microsatellites and is positioned Figure 1 Most significant individual haplotype P-values from previous association studies of NRG1 and schizophrenia or bipolar disorder. The P-values of the most significant haplotypes are given for each study reporting significant association between NRG1 and schizophrenia 7,[23][24][25][26][29][30][31][32][33] or bipolar disorder. 24 Williams et al 28 is not included as this sample was not significant when reanalysed with an increased control sample.…”

Section: Introductionmentioning

confidence: 99%

“…24 Williams et al 28 is not included as this sample was not significant when reanalysed with an increased control sample. 24 Yang et al 30 and Hall et al 29 reported P-values as less than a defined threshold, in these cases the threshold value is used. close to Hs.97362, an expressed sequence tag (EST) cluster of unknown function, within intron 1 of NRG1.…”

Section: Introductionmentioning

confidence: 99%

“…A South African Caucasian Afrikaner study 29 and five studies of the Han Chinese reported significant association of haplotypes with schizophrenia, both for Hap ICE markers and for other markers located in the region of Hap ICE and elsewhere ( Figure 1). [30][31][32][33] However, one report on the Han Chinese, one from the USA and a study from Japan failed to detect association.…”

Section: Introductionmentioning

confidence: 99%

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Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

et al. 2006

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Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P = 0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P = 0.00032), bipolar disorder (P = 0.0011), and the combined case group (P = 0.0017). This region includes the 5 0 exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P > 0.05). Region B contains a haplotype associated with both schizophrenia (P = 0.00014), and the combined case group (P = 0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P = 0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P = 0.024 and P = 0.016, respectively). It spans a B136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3 0 exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.

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Biological Validation of Increased Schizophrenia Risk With NRG1, ERBB4, and AKT1 Epistasis via Functional Neuroimaging in Healthy Controls

Nicodemus¹,

Law²,

Radulescu³

et al. 2010

Arch Gen Psychiatry

117

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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 We sought to examine epistasis between NRG1 and selected NMDA-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, 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 SNPs and case-control status; epistatic association between SNPs and the BOLD physiological response during working memory measured by functional magnetic resonance imaging (fMRI). RESULTS We observed interaction between NRG1 5’ and 3’ SNPs: rs4560751-rs3802160 (likelihood ratio test (LRT) p=0.00020) and schizophrenia which was validated using fMRI of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in dorsolateral prefrontal cortex (DLPFC) (p=0.015, FWE corrected). We observed epistasis between NRG1 (rs10503929; Val1066Ile) and its receptor ERBB4 (rs1026882; LRT p=0.035); a three-way interaction with these two SNPs and AKT1 (rs2494734) was also observed (OR=27.13; 95% confidence interval 3.30, 223.03; LRT p=0.042). These same two- and three-way interactions were further biologically validated via fMRI: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these two together with AKT1, were disproportionately less efficient in DLPFC processing. Lower-level interactions were not observed between NRG1/ERBB4-AKT1 in association or neuroimaging, consistent with biological evidence that NRG1-ERBB4 interaction modulates downstream AKT1 signaling. CONCLUSIONS Our data suggest complex epistatic effects implicating a NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.

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The contribution of three strong candidate schizophrenia susceptibility genes in demographically distinct populations

Cited by 101 publications

References 32 publications

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

Biological Validation of Increased Schizophrenia Risk With NRG1, ERBB4, and AKT1 Epistasis via Functional Neuroimaging in Healthy Controls

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