A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5×10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6×10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0×10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR= 1.08, P= 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N= 609, OR= 1.09, P= 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P= 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

To determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case-control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5 0 end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAP China 1 ), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P ¼ 0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAP China 2 ) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P ¼ 0.003, rr 2.2) and was also significant using parental controls only (P ¼ 0.0047, rr 2.1). A four-marker haplotype at the 3 0 end of the NRG1 gene, HAP China 3 , was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P ¼ 0.000042, rr ¼ 2.0) but was not significant in the case-control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese. Keywords: 8p; linkage; glial growth factor; psychosis; genetics; transmission; family Schizophrenia is a debilitating brain disease that affects up to 1% of the population worldwide. There is no cure, and treatments, which are mainly based on antagonism of dopamine, serotonin and other neurotransmitter receptors in the brain, are only partially effective. Although the aetiology of schizophrenia is not well understood, there is longstanding evidence of a genetic component, and recent twin studies place the heritability of schizophrenia at more than 80%. 1 Despite this high heritability, numerous candidate gene association studies have failed to identify susceptibility genes clearly. There are a variety of reasons for this failure, including probable locus and aetiological heterogeneity, characterised by the probable existence of numerous genes of small effect, the involvement of several biological pathways, lack of a pathophysiology to help with the selection of candidate genes, and methodological difficulties related to study design, statistical power and diagnostic validity and reliability.2 Linkage analysis has been more successful, with good evidence for genetic loci identified on chromosomes 8p, 22q, 13q and several other locations in the genome.3,4 These linkage findings have led to systematic genetic mapping efforts and positional candidate gene analysis of these loci. 5In a recent publication by Stefansson et al, 6 linkage to chromosome 8p followed by haplotype mappin...

The dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP 'A') in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia. Molecular Psychiatry (2005Psychiatry ( ) 10, 1037Psychiatry ( -1044Psychiatry ( . doi:10.1038 published online 26 July 2005 Keywords: psychosis; association; 6p; dysbindin; dystrobrevin Schizophrenia is a debilitating brain disease that affects up to 1% of the population worldwide. There is no cure and treatments, which are mainly based on antagonism of dopamine, serotonin and other neurotransmitter receptors in the brain, are only partially effective. Although the aetiology of schizophrenia is not well understood, there is longstanding evidence of a genetic component, and recent twin studies place the heritability of schizophrenia at more than 80%.