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Over 3000 candidate gene association studies have been performed to elucidate the genetic underpinnings of schizophrenia. However, a comprehensive evaluation of these studies’ findings has not been undertaken since the decommissioning of the schizophrenia gene (SzGene) database in 2011. As such, we systematically identified and carried out random-effects meta-analyses for all polymorphisms with four or more independent studies in schizophrenia along with a series of expanded meta-analyses incorporating published and unpublished genome-wide association (GWA) study data. Based on 550 meta-analyses, 11 SNPs in eight linkage disequilibrium (LD) independent loci showed Bonferroni-significant associations with schizophrenia. Expanded meta-analyses identified an additional 10 SNPs, for a total of 21 Bonferroni-significant SNPs in 14 LD-independent loci. Three of these loci (MTHFR, DAOA, ARVCF) had never been implicated by a schizophrenia GWA study. In sum, the present study has provided a comprehensive summary of the current schizophrenia genetics knowledgebase and has made available all the collected data as a resource for the research community.

The cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of the cytarabine (AraC) into a 1-β-D-arabinofuranosyluracil (AraU), an inactive metabolite that plays a crucial role in lowering the amount of AraC, a key chemotherapeutic drug, in the treatment of patients with acute myeloid leukemia (AML). In this study, we hypothesized that CDA polymorphisms were associated with the AraC metabolism for AML treatment and/or related clinical phenotypes. We analyzed 16 polymorphisms of CDA among 50 normal karyotype AML (NK-AML) patients, 45 abnormal karyotype AML (AK-AML) patients and 241 normal controls (NC). Several polymorphisms and haplotypes, rs532545, rs2072671, rs471760, rs4655226, rs818194 and CDA-ht3, were found to have a strong correlation with NK-AML compared with NC and these polymorphisms also revealed strong linkage disequilibrium with each other. Among them, rs2072671 (79A>C), which is located in a coding region and the resultant amino acid change K27Q, showed significant associations with NK-AML compared with NC (P=0.009 and odds ratio=2.44 in the dominant model). The AC and CC genotypes of rs2072671 (79A>C) were significantly correlated with shorter overall survival rates (P=0.03, hazard ratio=1.84) and first complete remission duration (P=0.007, hazard ratio=3.24) compared with the AA genotype in the NK-AML patients. Our results indicate that rs2072671 in CDA may be an important prognostic marker in NK-AML patients.

Body Mass Index (BMI) is widely regarded as an important clinical trait for obesity and other diseases such as Type 2 diabetes, coronary heart disease, and osteoarthritis. This study uses 6,011 samples of genotype data from ethnic Korean subjects. The data was retrieved from the Korea Association Resource. To identify the BMI-related markers within the Korean population, we collected genome-wide association study (GWAS) markers using a GWAS catalog and also obtained other markers from nearby regions. Of the total 6,011 samples, 5,410 subjects were used as part of a single nucleotide polymorphism (SNP) selection set in order to identify the overlapping BMI-associated SNPs within a 10-fold cross validation. We selected nine SNPs ( ( ), ( ), (located near ), (located near ), ( ), ( ), ( ), ( ), and (located near ) to assist in BMI prediction. The calculated weighted genetic risk scores based on the selected 9 SNPs within the SNP selection set were applied to the final validation set consisting of 601 samples. Our results showed upward trends in the BMI values (  < 0.0001) within the 10-fold cross validation process for  > 0.22. These trends were also observed within the validation set for all subjects, as well as within the validation sets divided by gender (  < 0.0001,  > 0.46). The set of nine SNPs identified in this study may be useful for prospective predictions of BMI.

Among central nervous system (CNS) tumors, gliomas are the most prevalent type of tumor. Single nucleotide polymorphisms (SNPs) in telomerase reverse transcriptase ( TERT ) gene have been identified as risk loci for gliomas by previous genome-wide association studies (GWAS). We examined association between TERT variants and glioma risk in a Korean population. For a case-control study, a total of 32 TERT SNPs from 317 patients with glioma and 480 population-based controls were genotyped. Logistic regression was used for statistical analysis of the link between TERT SNPs and risk of glioma. In this study, eight TERT variants, including four glioma-associated variants reported in previous studies, showed significant association with the risk of glioma. Conditional and stepwise analyses were conducted to validate independent associations in the group of the eight variants. Both analyses identified an intronic variant ( rs56345976 ) as the causal variant among the eight variants. Glioma subgroup analyses indicate that rs56345976 variant is associated with the risk of WHO grade 4, glioblastoma, isocitrate dehydrogenase (IDH) wild-type, and 1p/19q non-codeletion glioma. This study presents a profound comprehension of the relationship between TERT variants and the risk of glioma. Further studies of this variant are required to investigate its effect on glioma susceptibility.

Knowledge regarding the genetic risk loci for gestational diabetes mellitus (GDM) is still limited. In this study, we performed a two-stage genome-wide association analysis in Korean women. In the stage 1 genome scan, 468 women with GDM and 1,242 nondiabetic control women were compared using 2.19 million genotyped or imputed markers. We selected 11 loci for further genotyping in stage 2 samples of 931 case and 783 control subjects. The joint effect of stage 1 plus stage 2 studies was analyzed by meta-analysis. We also investigated the effect of known type 2 diabetes variants in GDM. Two loci known to be associated with type 2 diabetes had a genome-wide significant association with GDM in the joint analysis. rs7754840, a variant in CDKAL1, had the strongest association with GDM (odds ratio 1.518; P=6.65×10(-16)). A variant near MTNR1B, rs10830962, was also significantly associated with the risk of GDM (1.454; P=2.49×10(-13)). We found that there is an excess of association between known type 2 diabetes variants and GDM above what is expected under the null hypothesis. In conclusion, we have confirmed that genetic variants in CDKAL1 and near MTNR1B are strongly associated with GDM in Korean women. There seems to be a shared genetic basis between GDM and type 2 diabetes.

Objective Crohn's disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations. Methods We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls. Results We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10−14), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10−10) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10−9), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10−12) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10−5)) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans. Conclusions Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.

Aspirin-exacerbated respiratory diseases (AERD) are associated with the metabolism of arachidonic acid. FPR2 (formyl peptide receptor2) is a high-affinity ligand receptor for potent anti-inflammatory lipid metabolites: lipoxins. Thus, functional alterations of the FPR2 may contribute to AERD. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in the FPR2 and AERD. Asthmatics were categorized into AERD <15% decreases in forced expiratory volume in one second (FEV(1)), and/or naso-ocular reactions after oral aspirin challenge (n=170) and aspirin-tolerant asthma (ATA, n=268). In all, 11 SNPs were genotyped. FPR2 protein expressions on CD14-positive monocytes in peripheral blood were measured using flow cytometric analysis. We performed RT-PCR of the FPR2 mRNA expressed by peripheral blood mononuclear cells. Logistic regression analysis showed that the minor allele frequency of FPR2 -4209T>G (rs1769490) in intron 2 was significantly lower in the AERD group (n=170) than in the ATA group (n=268) (P=0.006, P(corr)=0.04, recessive model). The decline of FEV(1) after aspirin challenge was significantly lower in the subjects with GG homozygotes of FPR2 -4209T>G than those with the other genotypes (P=0.0002). Asthmatic homozygotes for FPR2 -4209T>G minor allele exhibited significantly higher FPR2 protein expression in CD14-positive monocytes than did those with the common allele of FPR2 -4209T>G allele (P=0.01). There was no difference in the expression of the wild form and the exon 2 deleted variant form of FPR2 gene according to the genotypes of FPR2 -4209T>G. The minor allele at FPR2 -4209T>G may have a protective role against the development of AERD, via increase of FPR2 protein expression in inflammatory cells.

Masato Kasuga and colleagues and Shiro Maeda and colleagues each report the independent identification of SNPs in KCNQ1 associated with type 2 diabetes in the Japanese population. Each group replicated the associations in other populations of East Asian and European descent. We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1 , and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest P value (6.7 × 10 −13 , odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 × 10 −42 (OR = 1.40; 95% CI = 1.34–1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of β-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.

Implication of Genetic Variants Near TCF7L2 , SLC30A8 , HHEX , CDKAL1 , CDKN2A/B , IGF2BP2 , and FTO in Type 2 Diabetes and Obesity in 6,719 Asians Maggie C.Y. Ng 1 , Kyong Soo Park 2 , Bermseok Oh 3 , Claudia H.T. Tam 1 , Young Min Cho 2 , Hyoung Doo Shin 4 , Vincent K.L. Lam 1 , Ronald C.W. Ma 1 , Wing Yee So 1 , Yoon Shin Cho 3 , Hyung-Lae Kim 3 , Hong Kyu Lee 2 , Juliana C.N. Chan 1 5 and Nam H. Cho 6 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China 2 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea 3 Center for Genome Science, National Institute of Health, Seoul, Korea 4 Laboratory of Genomic Diversity, Department of Life Science, Sogang University, Seoul, Korea 5 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China 6 Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea Corresponding author: Maggie C.Y. Ng, maggieng{at}cuhk.edu.hk Abstract OBJECTIVE— Recent genome-wide association studies have identified six novel genes for type 2 diabetes and obesity and confirmed TCF7L2 as the major type 2 diabetes gene to date in Europeans. However, the implications of these genes in Asians are unclear. RESEARCH DESIGN AND METHODS— We studied 13 associated single nucleotide polymorphisms from these genes in 3,041 patients with type 2 diabetes and 3,678 control subjects of Asian ancestry from Hong Kong and Korea. RESULTS— We confirmed the associations of TCF7L2 , SLC30A8 , HHEX , CDKAL1 , CDKN2A / CDKN2B , IGF2BP2 , and FTO with risk for type 2 diabetes, with odds ratios ranging from 1.13 to 1.35 (1.3 × 10 −12 < P unadjusted < 0.016). In addition, the A allele of rs8050136 at FTO was associated with increased BMI in the control subjects ( P unadjusted = 0.008). However, we did not observe significant association of any genetic variants with surrogate measures of insulin secretion or insulin sensitivity indexes in a subset of 2,662 control subjects. Compared with subjects carrying zero, one, or two risk alleles, each additional risk allele was associated with 17% increased risk, and there was an up to 3.3-fold increased risk for type 2 diabetes in those carrying eight or more risk alleles. Despite most of the effect sizes being similar between Asians and Europeans in the meta-analyses, the ethnic differences in risk allele frequencies in most of these genes lead to variable attributable risks in these two populations. CONCLUSIONS— Our findings support the important but differential contribution of these genetic variants to type 2 diabetes and obesity in Asians compared with Europeans. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 13 May 2008. M.C.Y.N., K.S.P., and B.O. contributed equally to this work. H.K.L., J.C.N.C., and N.H.C. contributed equally to this work. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 30, 2008. Received November 8, 2007. DIABETES

Gliomas are the most common primary tumors in the brain and spinal cord. In previous GWASs, SNPs in epidermal growth factor receptor ( EGFR ) have been reported as risk loci for gliomas. However, EGFR variants associated with gliomas in the Korean population remain unstudied. This study explored the association of EGFR SNPs with the risk of glioma. We genotyped 13 EGFR exon SNPs in a case–control study that included 324 Korean patients diagnosed with glioma and 480 population-based controls. Statistical analyses of the association between EGFR SNPs and glioma risk were conducted using logistic regression. Both stepwise analysis and conditional logistic analysis were performed to identify independent associations among genotyped variants. We confirmed that two SNPs ( rs2227983, rs1050171 ) were significantly associated with glioma ( rs2227983 : odds ratio = 1.42, P corr  = 0.009; rs1050171 : odds ratio = 1.68, P corr  = 0.005). Additionally, the stepwise analysis and conditional logistic analysis indicated that both SNPs created variants with independent genetic effects. This study is the first to show evidence that functional variants of EGFR , namely, rs2227983 (K521R) and rs1050171 (Q787Q), are associated with an increased risk of glioma in the Korean population. Future work should confirm the functional association between EGFR variants and glioma.