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Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P=0.009–0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.Molecular Psychiatry (2007) 12, 195–205. doi:10.1038/sj.mp.4001906; published online 10 October 2006 [ABSTRACT FROM AUTHOR]

The MPZL1/PZR gene has been mapped to 1q23.3, located in close proximity to a recognized schizophrenia susceptibility locus. Recently, the MPZL1/PZR gene has been found to be significantly upregulated in schizophrenia brain tissue and to play an important role in cell signaling, thus indicating that MPZL1/PZR could be a potential schizophrenia marker. To test this hypothesis, we selected three single nucleotide polymorphisms (SNPs) for genotyping in 523 Han Chinese trios. We found that two individual SNPs were significant at the Bonferroni's corrected significance level P<0.017: rs3767444 (χ2=6.299, P=0.0121) and rs2051656 (χ2=9.856, P=0.0017). Haplotype transmission/disequilibrium tests revealed a significant association with the disease (global P-value=1.064 × 10−6), but no specific transmission distortions. Thus, we propose that the MPZL1/PZR gene may be important in the predisposition to schizophrenia among Han Chinese.Molecular Psychiatry (2006) 11, 748–751. doi:10.1038/sj.mp.4001841; published online 9 May 2006 [ABSTRACT FROM AUTHOR]

The etiology of schizophrenia is unclear, although family, twin, and linkage studies implicate genetic factors. Here, we identified adenomatous polyposis coli (APC), a tumor suppressor gene, as a risk factor for schizophrenia. We compared leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray. APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, we measured expression levels of APC in the leukocytes from 30 relapse patients taking antipsychotic medication, 29 first-episode drug-naïve patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC is located at 5q21–22, which has been previously reported to be linked with schizophrenia. Further, we performed the transmission disequilibrium test (TDT) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent–offspring trios of Chinese descent. We analyzed three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC. TDT showed that the three SNPs are significantly associated with schizophrenia (TDT χ2=4.23, P<0.05; 4.15, P<0.05; 8.49 P<0.01, respectively; HHRRχ2=5.54, P<0.05; 4.40, P<0.05; 9.79, P<0.01, respectively). We found a significant association between the APC haplotypes from rs2229992–rs42427–rs465899 and schizophrenia (Global χ2=44.376,df=7, P<0.001). The C–A–T haplotype has a frequency of more than 57% and has a strong association with schizophrenia (χ2=15.04, P<0.001). These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia.Molecular Psychiatry (2005) 10, 669–677. doi:10.1038/sj.mp.4001653 Published online 15 March 2005 [ABSTRACT FROM AUTHOR]

Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism.Molecular Psychiatry (2005) 10, 572-580. doi:10.1038/sj.mp.4001605 Published online 2 November 2004 [ABSTRACT FROM AUTHOR]