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Although large-scale genome-wide association studies (GWASs) have revealed the genetic architecture of schizophrenia, these studies have mainly focused on populations of European ancestry. This study aimed to identify common genetic variants associated with schizophrenia in the Korean population and evaluate the performance of polygenic risk scores (PRSs) derived from large-scale GWASs across ancestries. In the Korean psychiatric GWAS project (KPGP), seven academic institutes and their affiliated hospitals across South Korea recruited a cohort of 1670 patients with DSM-IV-defined schizophrenia and 2271 healthy controls. A total of 6690,822 SNPs were tested for association with schizophrenia. We identified one previously unreported genome-wide significant locus rs2423464 (P = 2.83 × 10 -11 ; odds ratio = 1.65; 95 % confidence interval = 1.43-1.91, minor allele frequency = 0.126). This variant was also associated with increased lysosomal-associated membrane protein family member 5 (LAMP5) gene expression. The PRS derived from the meta-analysis results of East Asian and European GWASs explained a larger proportion of the phenotypic variance in the Korean schizophrenia sample than the PRS of an East Asian or European GWAS. (R 2 = 0.073 for meta-analysis; 0.028 for East Asian GWAS; 0.037 for European GWAS). GWASs involving diverse ethnic groups will expand our understanding of the genetic architecture of schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

ST8SIA2 and NCAM1 are functionally related genes forming polysialic acid (PSA) - neural cell adhesion molecule (NCAM) complex in suprachiasmatic nucleus (SCN), the regulating site of circadian biological rhythm. In this study, the relationship of ST8SIA2 and NCAM1 with circadian and seasonal rhythms of human behavior was explored. Subjects were 261 healthy Korean adults who were free of any history of clinically significant psychiatric symptoms. The phenotypes were circadian preference and seasonal change of mood and behavior (seasonality) measured by the Composite Scale of Morningness and the Seasonal Pattern Assessment Questionnaire, respectively. Thirty-four single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and 15 SNPs of NCAM1 were analyzed. A nominally significant association with seasonality and circadian preference was observed in 21 variants of both genes. After corrections for multiple testing, associations of 8 SNPs of ST8SIA2 and 2 SNPs of NCAM1 with seasonality remained significant. Some of these SNPs were also associated with psychiatric disorders in previous studies. This study demonstrated a meaningful and/or suggestive evidence of association between behavioral phenotypes reflecting human biological rhythm and two interplaying genes involved in the plasticity of SCN's neuronal network.

Background: Findings from family studies and recent genome-wide association studies have indicated overlap in the risk genes between schizophrenia and bipolar disorder (BD). After finding a linkage between the ST8SIA2 (ST8 alpha-N-acetyl-neuraminide alpha-2, 8-sicalyltransferase 2 gene) locus (15q26) and mixed families with schizophrenia and BD, several studies have reported a significant association between this gene and schizophrenia or BD. We investigated the genetic association between ST8SIA2 and both schizophrenia and BD in the Korean population., Methods: A total of 582 patients with schizophrenia, 339 patients with BD, and 502 healthy controls were included. Thirty-one tag single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and three other SNPs showing significant associations in previous studies were genotyped. The associations were evaluated by logistic regression analysis using additive, dominant, and recessive genetic models., Results: Fourteen of 34 SNPs showed a nominally significant association (p < 0.05) with at least one diagnostic group. These association trends were strongest for the schizophrenia and combined schizophrenia and bipolar I disorder (BD-I) groups. The strongest association was observed in rs11637898 for schizophrenia (p = 0.0033) and BD-I (p = 0.0050) under the dominant model. The association between rs11637898 and the combined schizophrenia and BD-I group (p = 0.0006, under the dominant model) remained significant after correcting for multiple testing., Discussion: We identified a possible role of ST8SIA2 in the common susceptibility of schizophrenia and BD-I. However, no association trend was observed for bipolar II disorder. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.

Background: The histology of atopic dermatitis includes dilated, tortuous vessels within the papillary dermis and perivascular edema., Method: This study included 1120 case-control samples (646 AD patients and 474 normal controls), for which we genotyped 34 SNPs from four VEGF family genes and the FLT4 gene. For the rs11607007 SNP in the VEGFB gene and three SNPs (rs10085109, rs3736062, and rs11949194) in the FLT4 gene, which had significant p-values in the initial stage, were further investigated using 1132 independent samples (440 AD patients and 692 normal controls)., Result: Of the four SNPs, rs10085109 in the FLT4 gene was only significantly associated with the AD phenotype in both initial and replication samples. Although no SNPs in the VEGFA gene were significantly associated with AD, the rs2010963 SNP had a marginally significant effect on log-eosinophil counts., Conclusion: The rs10085109 SNP in the FLT4 gene were associated with susceptibility to AD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Backgrounds/aims: Metastatic tumour antigen 1 (MTA1) promotes angiogenesis by stabilizing hypoxia-inducible factor-1α (HIF-1α), which is closely associated with frequent postoperative recurrence and poor survival in patients with HCC. In this study, we determined single nucleotide polymorphisms (SNPs) in angiogenesis-related genes that are associated with MTA1 overexpression in HCC tissues., Methods: A total of 376 patients with HCC who had received curative surgical resection or liver transplantation were enrolled (312/21/43; HBV/HCV/NBNC). MTA1 expression was determined via immunohistochemistry. Thirty-three common SNPs sites (frequency ≥5%) in the angiogenic protein gene that are closely connected to one another were selected, including MTA1, VEGF, HIF-1α, FGF-2, and IGF-II., Results: Expression of MTA1 was detected in 120 HCC tissues (31%). An A allele at position IVS4-81G/A of the MTA1 gene (P = 0.016) and the TT genotype at position +12916C of the VEGF gene (P = 0.023) were significantly associated with MTA1 overexpression. However, the TT genotype at position -13021C (P = 0.011) and the haplotypes CT-CT (-11228C; -13021C) of the IGF-II gene (P(cor) = 0.033) were more common in patients with MTA1-negative HCC. Using multivariate analysis, the A allele at IVS4-81G/A in MTA1 gene (P = 0.015) and a T allele (TT+CT genotype) at -13021C in IGF-II (P = 0.002) were independent risk factors in HCC recurrence after curative surgical resection., Conclusions: The genetic polymorphisms IVS4-81G/A in MTA1 and +12916C in VEGF genes were correlated with MTA1 overexpression. The SNPs in MTA1 and IGF-II genes may be important risk factors for the recurrence of HCC., (© 2011 John Wiley & Sons A/S.)

Background: The genes encoding IL-9 and IL-9R have recently been implicated in the genetic basis of asthma and allergy. Although studies performed on transgenic and knockout mice have shown conflicting results, no evidence of skin changes has ever been reported in these animals., Objective: To find association of the SNPs in IL-9 and IL-9R genes and interaction of these genes in atopic dermatitis., Method: We genotyped 5 SNPs from the IL-9 and IL-9R genes of 1090 subject samples (631 AD patients and 459 normal controls). A luciferase assay was then performed for the rs31563 (-4091G/A) SNP located in the IL-9 gene promoter region., Result: The rs31563 (-4091G/A) SNP in the IL-9 gene was significantly associated with the AD phenotype, especially allergic-type AD. In the luciferase assay, the rs31563 G construct was observed to have 1.54 times higher activity than the rs31563 A construct. Although no association was found between SNPs in IL-9R gene and AD, the rs3093467 SNP showed association with non-allergic AD. In the gene-gene interaction analysis, we found that IL-9/IL-9R genotype rs31563 GG/rs3093467 TT conveyed a greater risk for AD phenotype development., Conclusion: Significant evidence exists to suggest that the rs31563 SNP (-4091G/A) located in the IL-9 gene is associated with an increased susceptibility to AD. Similarly, the rs3093467 SNP in IL-9R gene seems to be associated with an increased risk for developing non-allergic AD. In a subsequent gene-gene interaction analysis, the rs31563 GG/rs3093467 TT genotype combination (IL-9/IL-9R) was found to exert a synergistic effect in the development of the AD phenotype. As the classes of helper T cells are diverse and the function of IL-9 cytokine has not been fully described, the cutaneous function of IL-9 needs to be further explored in future studies., (Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Clinical studies, including twin studies, support the concept that the risk of atopic dermatitis (AD) may be mediated through skin-specific genes, rather than simply through systemic immune or atopy risk genes. The SPINK5 gene is expressed on epithelial surfaces and may provide protection against other allergenic serine proteases. Mutations in the SPINK5 gene result in Netherton syndrome, a disorder characterised by AD, ichthyosis, and elevated serum IgE levels. We genotyped 21 single nucleotide polymorphisms (SNPs) from the SPINK5 gene for 1090 case-control samples (631 patients with AD and 459 normal controls) and analysed the SNPs and haplotypes in this gene and also searched for gene-gene interactions between SPINK5 and the DEFB1 gene that we previously reported. Six SNPs [rs17718511 (P = 0.026), rs17860502 (P = 0.024), KN0001820 (P = 0.045), rs60978485 (P = 0.007), rs17718737 (P = 0.02), and rs1422985 (P = 0.038)] and the haplotype TAA (rs60978485, rs6892205, rs2303064; P = 0.023) in the SPINK5 gene showed significant different allelic or genotypic distributions between the AD group and the control group. We also found that four SNPs [rs17718511 (P = 0.033), rs17860502 (P = 0.031), rs60978485 (P = 0.005), rs17718737 (P = 0.023)] and the haplotype TAA (P = 0.02) in the SPINK5 gene showed associations with the susceptibility of the allergic type of AD (ADe). In addition to this finding, we speculate that the SNPs from DEFB1 and SPINK5 affect the individual susceptibility to development of ADe in an additive manner. This study provides evidence for a significant interaction between allergens and the SPINK5 gene that may contribute to ADe susceptibility., (© 2010 John Wiley & Sons A/S.)

Background: The acute skin lesions of atopic dermatitis (AD) are associated with Th2 cells; however, the chronic skin lesions of AD are associated with Th1 cells via the action of IL-12., Objective: We evaluated the associations of single nucleotide polymorphisms (SNPs) and haplotype in the IL-12 and IL-12 receptor genes, and determined the gene-gene interactions between the SNPs of these genes and the SNPs of the IL-18 gene that we previously reported., Method: We genotyped 24 SNPs from 4 IL-12/IL-12R genes for 1089 case-control samples (631 AD patients and 458 normal controls). We measured the serum IL-12 concentrations in 89 individuals (79 AD patients and 10 controls) by ELISA. We analyzed the SNPs and haplotypes in each gene and also searched for the gene-gene interactions., Result: The rs582504 (IVS-798A/T) SNP and the haplotype TA (rs582054 and rs2243151) in the IL-12A gene, and the rs438421 (IVS12+1266T/C) SNP and the haplotype CCA (rs375947, rs438421, and rs1870063) in the IL-12RB1 gene were significantly associated with the AD phenotype. We showed that the rs438421 polymorphism in the IL-12RB1 (TT) gene and the rs2066446 polymorphism in the IL-12RB2 (AA) gene had a significant interaction to develop the ADe phenotype (allergic type of AD), and those individuals with the risk alleles, TT/AA/CC (IL-12RB1/IL-12RB2/IL-18), have more than a 10-fold increased risk to develop ADe., Conclusion: This study provides evidence for a significant interaction between the IL-12RB1 and IL-12RB2 genes that contribute to a 4-fold increased risk for developing ADe. In addition to the IL-12R interaction, we suggest that the IL-18 gene can significantly interact with the IL-12R gene to develop ADe. In addition to the interaction, the SNPs and haplotypes in the IL-12A and IL-12RB1 genes are independently and significantly associated with the AD phenotype, and especially with the ADe phenotype. This data may contribute to our understanding of AD genetic interactions and account for the additional risk of certain patients to develop AD., (2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

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., (2008 Wiley-Liss, Inc.)

Background: Toluene diisocyanate (TDI) is the most important cause of occupational asthma, but the genetic mechanism of TDI-induced asthma is still unknown., Objective: The objective of the study was to identify susceptibility alleles associated with the TDI-induced asthma phenotype., Methods: We conducted a genome-wide association study in 84 patients with TDI-induced asthma and 263 unexposed healthy normal controls using Affymetrix 500K SNPchip. We also investigated the relationships between genetic polymorphisms and transcript levels in Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with TDI-induced asthma enrolled in this study., Results: Genetic polymorphisms of CTNNA3 (catenin alpha 3, alpha-T catenin) were significantly associated with the TDI-induced asthma phenotype (5.84 x 10(-6) for rs10762058, 1.41 x 10(-5) for rs7088181, 2.03 x 10(-5) for rs4378283). Carriers with the minor haplotype, HT2 [GG], of two genetic polymorphisms (rs10762058 and rs7088181) showed significantly lower PC(20) methacholine level (P=0.041) and lower mRNA expression of CTNNA3 than non-carriers (P=0.040). A genetic polymorphism in the 3' downstream region of CTNNA3 (rs1786929), as identified by DNA direct sequencing, was significantly associated with the TDI-induced asthma phenotype (P=0.015 in recessive analysis model) and the prevalence of serum-specific IgG to cytokeratin 19 (P=0.031)., Conclusion: These findings suggested that multiple genetic polymorphisms of CTNNA3 may be determinants of susceptibility to TDI-induced asthma.

Objective: The aim of this study was to investigate whether IL12B polymorphisms might be associated with increased risk and invasiveness of cervical cancer in Korean women., Study Design: Peripheral blood samples from patients with invasive cervical cancer (n=154) and non-cancer controls (n=191) were used to detect three biallelic IL12B polymorphisms at IVS2 -912, IVS4 +314, 3'UTR +1188 sites by performing SNaPshot assay. Allelic frequencies, genotype distributions, and haplotype patterns in the case group were compared with those in the control group. The relationships between these polymorphisms and cancer invasiveness were also evaluated by collating the clinicopathologic parameters including FIGO stage, lymph node status, histologic type, and parametrial invasion. The used analytic methods are chi-square test and logistic regression analysis., Results: Allelic frequencies of cases (G, 0.853; A, 0.147) were not significantly different from controls (G, 0.796; A, 0.204) in IVS2 -912G/A SNP (P=0.054). GG genotype of IVS2 -912G/A SNP showed increased risk for cervical cancer compared with AA genotype (P=0.040). The IVS2 -912G:IVS4+314A haplotype, IVS2 -912G:IVS4 +314A:3'UTR +1188A haplotype, and IVS2 -912G:IVS4 +314A:3'UTR +1188C haplotype were also significantly associated with increased risk for cervical cancer. A subgroup analysis of the clinicopathologic parameters in cancer group also showed that there is no significant association between IL12B polymorphisms and cervical cancer invasiveness., Conclusions: This study suggests that IVS2 -912GG genotype and IVS2 -912G:IVS4 +314A haplotype of IL12B gene are associated with increased risk for cervical cancer in Korean women.

Background: Eosinophils are recruited into the affected tissue of asthma and atopic dermatitis (AD) patients. IL-5 and IL-5R are highly expressed in the AD skin lesions, yet the reported levels of IL-8 are controversial., Method: We genotyped 17 singlenucleotide polymorphisms (SNPs) from five genes of the 1120 case-control samples (646 AD and 474 controls). We measured the serum IL-5 concentrations in 87 individuals [36 ADe (AD extrinsic), 18 ADi (AD intrinsic) and 33 controls] by ELISA, and compared the results among these groups., Result: The rs2522411SNP and haplotype T-A in the IL-5 gene were significantly associated with the ADe. The serum IL-5 concentration was higher in the ADe than that in the ADi patients without any correlation with the rs2522411SNP. In the IL-5RA gene, the rs334809SNP showed a weak association with AD, and the rs6771148SNP and the haplotype T-C-T of the three adjacent tagged SNPs had an effect on the blood eosinophil counts and the serum ECP levels in the AD patients. However, we could not detect any relationship between AD and the SNPs in the IL-8 and IL-8R genes., Conclusion: We found that the rs2522411SNP and the haplotype T-A in the IL-5 gene and the serum IL-5 levels were strongly associated with the allergic type of AD, but not with the nonallergic type of AD. The association of the rs6771148SNP and the haplotype T-C-T in the IL5RA gene with the blood eosinophil counts and the serum ECP levels indicates that the IL5RA gene has a role for controlling eosinophils in the peripheral blood.

Background: IL-18 is a proinflammatory cytokine that plays an important role for T-helper type 1 (Th1) and Th2 cytokine in the presence/absence of IL-12. It has been recently shown that human IL-18 plays a role in atopic dermatitis (AD) by enhancing IL-4 and IL-13 production and by stimulating the synthesis of IgE., Objective: We wanted to evaluate the associations of single-nucleotide polymorphism (SNP) and the haplotype in the IL-18 gene, hence we performed genotyping for the SNPs in the IL-18 gene in AD patients and normal controls., Method: We genotyped three SNPs from the IL-18 gene for the 1120 case-control samples (646 AD patients and 474 normal controls). We measured the serum IL-18, IL-4 and IL-13 concentrations in 74 individuals (25 ADe, 25 ADi and 24 controls) by performing ELISA., Result: The rs795467 SNP and haplotype T-T-C were significantly associated with AD, and especially between the ADe and normal control groups (P=0.03 and 0.01). The serum IL-18 concentration was higher in the AD group than in the normal controls without any correlation with the rs795467 polymorphism. We did not find any correlations between the serum IL-18 levels and the SCORing atopic dermatitis index, the blood eosinophil counts and the ECP, and there was no correlation between the serum IL-18 levels and the serum IL-4 and IL-13 levels., Conclusion: We found that the one SNP and the haplotype T-T-C were strongly associated with the allergic type of AD, but not with the non-allergic intrinsic type. These data support the hypothesis that IL-18 up-regulates IgE production, yet more experiments will be needed to prove the in vivo involvement of Th2 cytokine.

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., (Copyright 2006 Wiley-Liss, Inc.)