Genomic scan for genes predisposing to schizophrenia

Coon, Hilary; Jensen, Steve; Holik, John; Hoff, M.; Myles-Worsley, Marina; Reimherr, Frederick W.; Wender, Paul H.; Waldo, Merilyne; Freedman, Robert; Leppert, M.; Byerley, William

doi:10.1002/ajmg.1320540111

Cited by 163 publications

(103 citation statements)

References 71 publications

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“…14 Although CYP1A2 by itself has never been implicated in pathogenesis of schizophrenia, the neighboring loci (15q13-15) have all been implicated. [20][21][22][23] CYP1A2 (15q21) is located in the vicinity of nicotinic receptors CHRNA3, CHRNA5 and CHRNB4, localized at 15q24. CYP1A2 mRNA has been detected in the rat brain (cortex, cerebellum, brain stem, thalamus, hippocampus and striatum 24 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

Tiwari

Deshpande²,

Lerer

et al. 2006

Pharmacogenomics J

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Tardive dyskinesia (TD) is an iatrogenic disorder observed in B20-30% of schizophrenia patients on long-term treatment with typical antipsychotic drugs. CYP1A2 is involved in the metabolism of atypical antipsychotic drugs such as clozapine and olanzapine. It is not directly involved in the metabolism of typical antipsychotic drugs, but gains importance when the schizophrenia patients are under long-term chronic treatment, acting as a low-affinity high-capacity metabolizing enzyme. In this study, we have completely sequenced the coding region to ascertain the presence of common coding polymorphisms and their role if any in susceptibility to TD and schizophrenia. Four previously reported polymorphisms, CYP1A2*1F (intron A), rs2472304 & rs3743484 (intron D) and rs2470890 (CYP1A2 1545 C4T) in exon 7 were identified. We further investigated whether the CYP1A2 1545 C4T polymorphism has any role to play in susceptibility to TD and in schizophrenia per se. Association of this single nucleotide polymorphism with TD (P ¼ 0.03) and schizophrenia (P ¼ 0.04) was observed, but was rendered insignificant after corrections for multiple comparisons.

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Section: Discussionmentioning

confidence: 99%

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

Tiwari

Deshpande²,

Lerer

et al. 2006

Pharmacogenomics J

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“…Chromosome 15q13-15 has been found to be associated with schizophrenia in genome wide scans [30][31][32] although the criteria for linkage were fulfilled in only one study using a subtype Periodic Catatonia (15q15 at position 35.3 cM, LOD score ¼ 3.57, P ¼ 2.6 Â 10 À5 ). 32 Freedman et al 33 reported positive linkage of the abnormality in P50 suppression with D15S1360, a dinucleotide repeat present o120 kbp from the 5 0 end of the coding region of the alpha 7-nicotinic receptor gene (CHRNA-7), assuming an autosomal dominant mode of transmission (LOD score ¼ 5.3, Y ¼ 0.0, Po0.0001 33 ).…”

Section: Association Of Cyp1a2 Polymorphisms With Tardive Dyskinesiamentioning

confidence: 99%

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

et al. 2004

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Understanding the pharmacogenetic basis of developing iatrogenic disorders such as Tardive Dyskinesia (TD) has significant clinical implications. CYP1A2, an inducible gene of the cytochrome P450 family of genes, has been suggested to contribute to the metabolism of typical antipsychotics in subjects with schizophrenia on long-term treatment, and has been considered as a potential candidate gene for development of TD. In this study, we have investigated the significance of CYP1A2 gene polymorphisms in TD susceptibility among chronic schizophrenia sufferers (n ¼ 335) from north India. TD was diagnosed in B29% (96/335) of these subjects. Of the 96 TD positives, 28 had been treated with typical antipsychotics alone, 23 with atypical antipsychotics alone and 45 patients had received both classes of drugs during the course of their illness. Out of the six SNPs tested, CYP1A2*2, *4, *5, *6 were found to be monomorphic in our population. CYP1A2*1C and CYP1A2*1F were polymorphic and were analyzed in the study sample. Since these two allelic variants lead to lesser inducibility among smokers, the smoking status of TD patients was also considered for all subsequent analysis. We observed increased severity of TD among TD-Y smokers, who were carriers of CYP1A2*1C (G4A) variant allele and had received only typical antipsychotic drugs (F(1,8) ¼ 9.203, P ¼ 0.016). No significant association of CYP1A2*1F with TD was observed irrespective of the class of drug they received or their smoking status. However, we found a significant association of CYP1A2*1F with schizophrenia (w 2 ¼ 6.572, df ¼ 2, P ¼ 0.037).

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“…Genotyping was performed using standard techniques. 21 Marker allele frequencies for the K1583 genome scan were estimated from 56 marry-in spouses taken from seven pedigrees. Marker allele frequencies for the chromosome 2 region were estimated from 94 marry-in spouses from all 17 typed pedigrees.…”

Section: Genotypingmentioning

confidence: 99%

Evidence for a chromosome 2p13–14 schizophrenia susceptibility locus in families from Palau, Micronesia

et al. 1998

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A large multiplex schizophrenia pedigree ascertained from the Micronesian nation of Palau was genotyped with 406 microsatellite DNA markers evenly distributed throughout the genome. Assuming autosomal dominant inheritance, the highest genome-wide lod scores were found for DNA loci mapping to 2p13-14; the maximum lod score was 2.17 (theta = 0.05) at D2S441. A nonparametric APM analysis was also suggestive at D2S441 (APM score = 2.96, P = 0.011). Of the 14 affected cases in this extended family, eight share a large haplotype in this region spanning ෂ11 cM. When 16 other families containing 65 schizophrenic cases were typed in a follow-up study of this region, the maximum lod score remained positive (maximum at D2S441 1.69, theta = 0.20). APM results also remained positive at D2S441 for all 17 families (APM score = 4.87, P = 0.0006). The linkage and haplotype sharing results provide suggestive evidence for a 2p locus predisposing to schizophrenia in a subset of families in the Palauan population.

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Genomic scan for genes predisposing to schizophrenia

Cited by 163 publications

References 71 publications

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

Evidence for a chromosome 2p13–14 schizophrenia susceptibility locus in families from Palau, Micronesia

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