Recently, we identified neuregulin 1 (NRG1) as a susceptibility gene for schizophrenia in the Icelandic population, by a combined linkage and association approach. Here, we report the first study evaluating the relevance of NRG1 to schizophrenia in a population outside Iceland. Markers representing a core at-risk haplotype found in Icelanders at the 5' end of the NRG1 gene were genotyped in 609 unrelated Scottish patients and 618 unrelated Scottish control individuals. This haplotype consisted of five SNP markers and two microsatellites, which all appear to be in strong linkage disequilibrium. For the Scottish patients and control subjects, haplotype frequencies were estimated by maximum likelihood, using the expectation-maximization algorithm. The frequency of the seven-marker haplotype among the Scottish patients was significantly greater than that among the control subjects (10.2% vs. 5.9%, P=.00031). The estimated risk ratio was 1.8, which is in keeping with our report of unrelated Icelandic patients (2.1). Three of the seven markers in the haplotype gave single-point P values ranging from .000064 to .0021 for the allele contributing to the at-risk haplotype. This direct replication of haplotype association in a second population further implicates NRG1 as a factor that contributes to the etiology of schizophrenia.

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...

Migraine is a common form of headache and has a significant genetic component. Here, we report linkage results from a study in Iceland of migraine without aura (MO). The study group comprised patients with migraine recruited by neurologists and from the registry of the Icelandic Migraine Society, as well as through the use of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses were made and confirmed using diagnostic criteria established by the International Headache Society. A genome-wide scan with multipoint allele-sharing methods was performed on 289 patients suffering from MO. Linkage was observed to a locus on chromosome 4q21 (LOD=2.05; P=.001). The locus reported here overlaps a locus (MGR1) reported elsewhere for patients with migraine with aura (MA) in the Finnish population. This replication of the MGR1 locus in families with MO indicates that the gene we have mapped may contribute to both MA and MO. Further analysis indicates that the linkage evidence improves for affected females and, especially, with a slightly relaxed definition of MO (LOD=4.08; P=7.2 x 10(-6)).