Genome-widely significant evidence of linkage of schizophrenia to chromosomes 2p24.3 and 6q27 in an SNP-Based analysis of Korean families.

The present study reports the results of a genome-wide SNP linkage scan for schizophrenia in the Korean population. Fifty-six multiplex schizophrenia families were analyzed. Clinical evaluations on all subjects were consistently performed by raters in a single research team. Multipoint non-parametric linkage analysis was performed, and empirical simulations were generated to determine genome-wide significance. The authors found genome-widely significant evidence of linkage for schizophrenia to chromosomes 2p24.3 (NPL Z = 3.18) and 6q27 (NPL Z = 2.90). Six other chromosomal regions, that is, 3q24, 13q12.3, 18q22.3, 20p12.2, 4p14, and 1p36.12, yielded NPL Z scores of above 2.0 for either broad or narrow phenotype classes. Although linkage to these loci has not received prominent attention in studies on Caucasian families, multiple overlaps were observed between our loci (on 2p, 3q, and 13q) and linkage peaks generated from extended families in various isolated populations. Fine mappings and the detection of candidate genes within these regions are warranted.

Linkage of schizophrenia with chromosome 1q32 in Korean multiplex families.

Chromosome 1q contains a few loci for which modest evidence of linkage with schizophrenia has been reported in several independent studies. However, markers showing the peak linkage signal are dispersed over a large chromosomal region. In addition, inconsistent findings have been generated from different populations or different subgroups of the same populations. The purpose of the current study is to determine whether those loci are linked to schizophrenia in the Korean population. We investigated 46 Korean multiplex schizophrenia families, initially using 11 microsatellite markers spanning around 91 cM region of 1p22 approximately 42. In a non-parametric linkage analysis, D1S249 located on 1q32.1 showed statistical evidence suggestive of linkage. At the second stage analysis for narrowing down the region, four additional nearby markers were genotyped. In the single point analysis, we found another suggestive linkage signal at D1S2891. The highest NPL score of 2.67 (P = 0.0039) was obtained in the multi-point analysis. This study provides supportive evidence for linkage of chromosome 1q32 with schizophrenia.

Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population.

Chromosome 8p21-12 has been reported to be a susceptibility locus for schizophrenia based on genome-wide linkage scans. After neuregulin 1 (NRG1) was identified as a positional candidate gene for schizophrenia in this locus, several independent association studies have reported controversial results. To determine whether genetic variations in this locus are associated with schizophrenia in the Korean population, we investigated multiplex families and unrelated patients using linkage and association analyses. Seven microsatellite markers in 8p21-12 were genotyped for 40 families with schizophrenia, and a non-parametric linkage analysis was applied. The association study was performed with 242 unrelated schizophrenia patients and the same number of normal controls for three single nucleotide polymorphisms (SNPs), two microsatellite markers and their haplotypes. A significant linkage signal was observed on D8S1769, which is located 352 kb upstream of the 5' end of the first exon of NRG1 for two ("narrow" and "narrow with auditory hallucination (AH)") of the three adopted phenotype classes. In the association study, the G allele of SNP8NRG241930 was significantly in excess in the subgroup of patients with AHs. We also found haplotypes which were associated with schizophrenia with a protective effect. This study provides additional suggestive evidence for both the linkage and association of genetic variations on 8p12, a locus of NRG1, with schizophrenia. NRG1 might either play a role in the predisposition to schizophrenia or be in linkage disequilibrium (LD) with a causal locus of this illness.