Previous Genome-wide Association Study Data Research Articles

Identification of B-cell-related HSPG2 and CDSN as susceptibility loci for Kawasaki disease

Kawasaki disease (KD) is an acute pediatric vasculitis that predominantly affects children under the age of 5 years. To date, genome-wide association studies (GWAS) have identified several KD susceptibility genes (e.g., BLK, CD40, FCGR2A, BCL2L11, and IGHV), which are mainly involved in B cell immunity. In this study, we aimed to identify additional KD susceptibility genes mainly involved in B cell development and functions by analyzing our previous GWAS data and conducting a replication study using new sample. Initially, we selected 30 single nucleotide polymorphisms (SNPs) in B-cell-related genes that were significantly (P < 0.01) associated with KD in our previous GWAS analysis of 247 KD cases with complete type and 1,000 healthy controls. Replication study was performed by genotyping the new 837 KD case samples with Fluidigm system and comparing them with 3,553 control genotypes. Among the 30 candidate SNPs, two were significantly associated with KD (P < 0.001) in the replication study. An even greater association between these SNPs and KD was observed in the combined analysis of GWAS and replication samples: odds ratio (OR) = 1.97 (P = 8.61 × 10−6) for rs2270699 (nonsynonymous SNP: c.10588C > T, p.Arg3530Trp) in the heparan sulfate proteoglycan 2 (HSPG2) gene and OR = 1.28 (P = 1.34 × 10−6) for rs3130992 (intronic SNP) in both the corneodesmosin (CDSN) and psoriasis susceptibility 1 candidate 1 (PSORS1C1) genes. These results suggest that the B-cell-related genes, HSPG2 and CDSN or PSORS1C1, play a role in the development of KD.

Fine-Mapping of the Major Histocompatibility Complex Region Linked to Leprosy in Northern China.

Background: Leprosy is a chronic infectious skin and neurological disease, and genetic background is considered to be one of the major factors of risk. The major histocompatibility complex (MHC) region not only affects susceptibility to leprosy but also its development and outcome. Given the complex traits of the MHC region, variants and the potential mechanism by which HLA influences leprosy development need to be further explored. Methods: We extracted previous genome-wide association study data from the Northern Han Chinese population to perform HLA fine-mapping. Using the 1,000 Genome Project Phase 3 dataset as the reference panel, single-nucleotide polymorphisms (SNP), insertion and deletion (INDEL) and copy number variant (CNV) imputation were carried out. HLA classical alleles and amino acids in the MHC region were imputed using the HAN-MHC database. Further stepwise regression analysis was conducted to analyze independent signals of variants related to leprosy. Results: We identified four independent variants: esv3608598, rs7754498, rs3130781 and rs144388449. Among them, esv3608598 is a CNV and the first HLA CNV associated with leprosy risk. SNP annotation using RegulomeDB, HaploReg, and rVarBase showed that three SNPs are likely to affect the pathogenesis of leprosy. Conclusion: In summary, this is the first study to assess the association between HLA CNV and leprosy susceptibility in a Northern Han Chinese population. By fine mapping of the MHC region in this population, our findings provide evidence for the contribution of HLA to leprosy susceptibility.

Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis.

As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene–gene interaction networks enriched by those topmost pathways, we identified KDs—both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)—in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC.

Multi-Omics Data Analysis Uncovers Molecular Networks and Gene Regulators for Metabolic Biomarkers.

The insulin-like growth factors (IGFs)/insulin resistance (IR) axis is the major metabolic hormonal pathway mediating the biologic mechanism of several complex human diseases, including type 2 diabetes (T2DM) and cancers. The genomewide association study (GWAS)-based approach has neither fully characterized the phenotype variation nor provided a comprehensive understanding of the regulatory biologic mechanisms. We applied systematic genomics to integrate our previous GWAS data for IGF-I and IR with multi-omics datasets, e.g., whole-blood expression quantitative loci, molecular pathways, and gene network, to capture the full range of genetic functionalities associated with IGF-I/IR and key drivers (KDs) in gene-regulatory networks. We identified both shared (e.g., T2DM, lipid metabolism, and estimated glomerular filtration signaling) and IR-specific (e.g., mechanistic target of rapamycin, phosphoinositide 3-kinases, and erb-b2 receptor tyrosine kinase 4 signaling) molecular biologic processes of IGF-I/IR axis regulation. Next, by using tissue-specific gene–gene interaction networks, we identified both well-established (e.g., IRS1 and IGF1R) and novel (e.g., AKT1, HRAS, and JAK1) KDs in the IGF-I/IR-associated subnetworks. Our results, if validated in additional genomic studies, may provide robust, comprehensive insights into the mechanisms of IGF-I/IR regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for the associated diseases, e.g., T2DM and cancers.

A Whole-Genome Sequencing Association Study of Low Bone Mineral Density Identifies New Susceptibility Loci in the Phase I Qatar Biobank Cohort.

Bone density disorders are characterized by a reduction in bone mass density and strength, which lead to an increase in the susceptibility to sudden and unexpected fractures. Despite the serious consequences of low bone mineral density (BMD) and its significant impact on human health, most affected individuals may not know that they have the disease because it is asymptomatic. Therefore, understanding the genetic basis of low BMD and osteoporosis is essential to fully elucidate its pathobiology and devise preventative or therapeutic approaches. Here we sequenced the whole genomes of 3000 individuals from the Qatar Biobank and conducted genome-wide association analyses to identify genetic risk factors associated with low BMD in the Qatari population. Fifteen variants were significantly associated with total body BMD (p < 5 × 10−8). Of these, five variants had previously been reported by and were directionally consistent with previous genome-wide association study data. Ten variants were new: six intronic variants located at six gene loci (MALAT1/TALAM1, FASLG, LSAMP, SAG, FAM189A2, and LOC101928063) and four intergenic variants. This first such study in Qatar provides a new insight into the genetic architecture of low BMD in the Qatari population. Nevertheless, more studies are needed to validate these findings and to elucidate the functional effects of these variants on low BMD and bone fracture susceptibility.

Transcriptome-wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma.

Previous genome-wide association studies (GWAS) have identified multiple susceptible variants associated with persistent hepatitis B virus (HBV) infection. However, most of these variants are located in the noncoding regions, which make it difficult to determine the effective genes underlying these associations. We performed a two-stage study, in the first stage we integrated RNA sequencing data of liver tissues and high-density genotyping data from the Genotype-Tissue Expression (GTEx) project with our previous GWAS data to conduct a transcriptome-wide association study (TWAS) on HBV infection. Firstly, the cis-heritable genes were screened by a genetic relatedness matrix of genome-wide complex trait analysis (GCTA) from GTEx data. Then, the genetic expression of 2587 cis-heritable genes was predicted by restricted maximum likelihood (REML) of genome-wide efficient mixed-model association (GEMMA) in our GWAS data with 951 HBV carrier cases and 937 HBV cleared controls. Next, we investigated the associations between predictive expression levels and persistent HBV infection risk. Gene set enrichment analysis (GSEA) was applied to infer the function of the identified genes. To identify the causal single nucleotide polymorphisms (SNPs) of HBV infection risk, we conducted the expression quantitative trait loci (eQTL)-based stepwise logistic regression analysis in the regions around 1 Mb of these genes and validated the association between 994 health controls and 994 HBV-persistent infection cases by genotyping experiment. In the second stage, 1538 HBV-related hepatocellular carcinoma (HCC) cases and 1465 persistent HBV infection controls were collected to determine the effect of these variants on HBV-related HCC as well, which were examined by the additive model in logistic regression analysis. We identified seven genes associated with HBV infection. In the classic human leukocyte antigen (HLA) region, three novel genes BAK1, HLA-DOB and C4A (Z range from -3.95 to -3.64, P range from 7.84 × 10-5 to 2.00 × 10-4 ), as well as two genes (HLA-DPA1 and HLA-DPB1) were reported by previous GWAS. In the non-HLA region, immune related at newly identified loci, PARP9 (Z = 3.69, P = 2.20 × 10-4 ) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 3.80 × 10-4 ) as a target gene in addition to the reported non-cis-heritable gene UBE2L3. After further stepwise logistic regression analysis and validation, we identified eight variants independently associated with persistent HBV infection. Among those variants, the additive model showed that two SNPs associated with HBV-related HCC risk (rs9272714 and rs9394194, OR range from 1.20 to 1.25, P range from 1.19 × 10-4 to 3.97 × 10-4 ). By integrating transcriptome data, our study not only identified new susceptibility loci of persistent HBV infection but also determined the potential target genes at reported loci, which provided insight into the genetic aetiology of persistent HBV infection and related HCC.

Abstract LB-100: HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function

Abstract BACKGROUND: Genome-wide association studies (GWAS) have identified several genetic regions associated with risk of pancreatic ductal adenocarcinoma (PDAC) while the underlying mechanisms remain largely unknown. This study investigated the functions of genes in these genetic regions and their roles as potential biomarkers or therapeutic targets for PDAC. METHODS: We reanalyzed our previous GWAS data based on referring the 108 risk loci reported in published PDAC GWAS to seek for all susceptibility genes in the Chinese population and found 44 potential risk genes. A siRNA library was used to silence these genes in PDAC cell lines and the malignant phenotypes were examined by using a high content screen method followed by a series of functional assays. RESULTS: Among the 44 genes, HNF4G was the top one who’s silencing significantly repressed PDAC cell migration and invasion. Functional assays showed that HNF4G regulates cell-cell junction pathway, which may be the underlying mechanism for its action. HNF4G was upregulated by SMAD4 loss of function and frequently overexpressed in PDACs. PDAC cell metastasis promoted by the overexpression of HNF4G could be suppressed by metformin, and this effect was seen only in PDAC cells with SMAD4 loss of function, resulting in heterogeneous vulnerability of PDAC to the drug. CONCLUSION: HNF4G overexpression might result in metformin sensitivity in PDAC with SMAD4 loss of function and thus represent as a potential therapeutic target. Citation Format: Chengcheng Wang, Chen Wu, Dongxin Lin, Yupei Zhao. HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-100.

Finding the Missing Heritability of Genome-wide Association Study Using Genotype Imputation

Genome-wide association studies (GWAS) have identified thousands of genetic risk variants. However, these variants have explained relatively little of estimated heritability for most complex diseases. The 1000 Genomes Project is a good source to impute missing genotypes for previous GWAS data. Imputation based GWAS can identify more associated signals on a genomewide scale. These newmarkers can be potential sources of missing heritability. In this study, we did the genotype imputation on theWellcome Trust Case Control Consortium Phase I genotype data using 1000 genomes as reference. Then we estimated the phenotypic variance explained by all significant association signals. The results suggested that the proportions of phenotypic variance explained by genetic variants increased significantly when the new association variants identified through 1000 genome based imputation were included. These results were consistent with the hypothesis that larger number of variants that are yet to be identified as potential sources of missing heritability.

Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study.

DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls. Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases and 250 controls (n = 497) from the Genomic Psychiatry Cohort. Identification of differentially methylated positions across the genome in SZ cases compared with controls. Of the 689 case participants in the discovery set, 477 (69%) were men and 258 (37%) were non-African American; of the 645 controls, 273 (42%) were men and 419 (65%) were non-African American. In our replication set, cases/controls were 76% male and 100% non-African American. We identified SZ-associated methylation differences at 923 CpGs in the discovery set (false discovery rate, <0.2). Of these, 625 showed changes in the same direction including 172 with P < .05 in the replication set. Some replicated differentially methylated positions are located in a top-ranked SZ region from genome-wide association study analyses. This analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.

Endometrial vezatin and its association with endometriosis risk.

Do endometriosis risk-associated single nucleotide polymorphisms (SNPs) found at the 12q22 locus have effects on vezatin ( ITALIC! VEZT) expression? The original genome-wide association study (GWAS) SNP (rs10859871), and other newly identified association signals, demonstrate strong evidence for ITALIC! cis-expression quantitative trait loci (eQTL) effects on ITALIC! VEZT expression. GWAS have identified several disease-risk loci (SNPs) associated with endometriosis. The SNP rs10859871 is located within the ITALIC! VEZT gene. ITALIC! VEZT expression is altered in the endometrium of endometriosis patients and is an excellent candidate for having a causal role in endometriosis. Most of the SNPs identified from GWAS are not located within the coding region of the genome. However, they are likely to have an effect on the regulation of gene expression. Genetic variants that affect levels of gene expression are called expression quantitative trait loci (eQTL). Samples for genotyping and ITALIC! VEZT variant screening were drawn from women recruited for genetic studies in Australia/New Zealand and women undergoing surgery in a tertiary care centre. Coding variants for ITALIC! VEZT were screened in blood from 100 unrelated individuals (endometriosis-dense families) from the QIMR Berghofer Medical Research Institute dataset. SNPs at the 12q22 locus were imputed and reanalysed for their association with endometriosis. Reanalysis of endometriosis risk-association was performed on a final combined Australian dataset of 2594 cases and 4496 controls. Gene expression was performed on 136 endometrial samples. eQTL analysis in whole blood was performed on 862 individuals from the Brisbane Systems Genetics Study. Endometrial tissue-specific eQTL analysis was performed on 122 samples (eutopic endometrium) collected following laparoscopic surgery. VEZT protein expression studies employed ITALIC! n = 56 (western blotting) and ITALIC! n = 42 (immunohistochemistry) endometrial samples. The women recruited for this study provided blood and/or endometrial tissue samples in a hospital setting. Genomic DNA was screened for common and coding variants. SNPs of interest in the 12q22 region were genotyped using Agena MassARRAY technology or Taqman SNP genotyping assay. Gene expression profiles from RNA extracted from blood and endometrial tissue samples were generated using Illumina whole-genome expression chips (Human HT-12 v4.0). Whole protein extracted from endometrium was used for VEZT western blots, and paraffin sections of endometrium were employed for VEZT immunohistochemistry semi-quantitative analysis. A total of 11 coding variants of ITALIC! VEZT (including one novel variant) were identified from an endometriosis-dense cohort. Polymorphic coding and imputed SNPs were combined with previous GWAS data to reanalyse the endometriosis risk association of the 12q22 region. The disease association signal at 12q22 was due to coding variants in ITALIC! VEZT or ITALIC! FGD6 (FYVE, RhoGEF and PH domain-containing 6) and SNPs with the strongest signals were either intronic or intergenic. We found strong evidence for ITALIC! VEZT cis-eQTLs with the sentinel SNP (rs10859871) in blood and endometrium, where the endometriosis risk allele (C) was associated with an increase in ITALIC! VEZT expression. We could not demonstrate this genotype-specific effect on VEZT protein expression in endometrium. However, we did observe a menstrual cycle stage specific increase in VEZT protein expression in endometrial glands, specific to the secretory phase ( ITALIC! P = 2.0 × 10(-4)). In comparison to the blood sample datasets, the study numbers of endometrial tissues were substantially reduced. Protein studies failed to complement RNA results, also likely a reflection of the low study numbers in these experiments. ITALIC! In silico prediction tools used in this investigation are typically based on cell lines different to our tissues of interest, thus any functional annotations drawn from these approaches should be considered carefully. Therefore, functional studies on VEZT and related pathway components are still warranted to unequivocally implicate a causal role for VEZT in endometriosis pathophysiology. GWAS have proven to be very valuable tools for deciphering complex diseases. Endometriosis is a text-book example of a complex disease, involving genetic, lifestyle and environmental influences. Our focused investigation of the 12q22 region validates an association with increased endometriosis risk. Endometriosis risk SNPs (including rs10859871) located within this locus demonstrated evidence for ITALIC! cis-eQTLs on ITALIC! VEZT expression. By examining women who possess an enhanced genetic risk of developing endometriosis, we have identified an effect on ITALIC! VEZT expression and therefore a potential gene/gene pathway in endometriosis disease establishment and development. Funding for this work was provided by NHMRC Project Grants GNT1012245, GNT1026033, GNT1049472 and GNT1046880. G.W.M. is supported by the NHMRC Fellowship scheme (GNT1078399). S.J.H.-C. is supported by the J.N. Peters Bequest Fellowship. The authors declare no competing interests. N/A.

Variants in FSHB Are Associated With Polycystic Ovary Syndrome and Luteinizing Hormone Level in Han Chinese Women.

A recent genome-wide association study (GWAS) has identified three susceptibility loci (8p32.1, 11p14.1, and 9q22.32) for polycystic ovary syndrome (PCOS) in women of European ancestry. The 9q22.32 locus was previously found in our Chinese PCOS GWAS. Replication of the other two loci is necessary to determine whether the same variants confer risk to PCOS in Han Chinese women. This study aimed to investigate the effect of the European GWAS loci on PCOS susceptibility in Han Chinese women. This was a genetic association study at a university hospital in composed of 1601 PCOS cases and 1238 age-matched controls. Interventions and Main Outcome Measure: After screening of the regions that cover 500 kb upstream and downstream of the two single-nucleotide polymorphisms (SNPs) using our previous Chinese GWAS data, rs11031010, located in the region of follicle-stimulating hormone B polypeptide (FSHB) gene, was selected for further replication. The other SNPs near rs804279 (GATA4/NEIL2) were excluded based on our previous GWAS data. Then, the variant rs11031010 was genotyped in an independent cohort and the associations with PCOS, endocrine and metabolic traits were assessed. In the current replication study, rs11031010 was associated with PCOS in Han Chinese women (P = 2.76 × 10(-3)), even after adjustment for age and body mass index. Meta-analysis with our previous GWAS data showed that the allele frequency difference of rs11031010 between PCOS and controls reached genome-wide significance (P = 4.27 × 10(-8)). PCOS women with AA and AC genotypes had a significantly higher LH level than individuals carrying the CC genotype (P =1.60 × 10(-4)). The genetic risk score based on sixteen total Chinese PCOS-risk SNPs, calculated by total number of risk alleles for each subject, was associated with the diagnosis of PCOS (P < 1.00 × 10(-4)). Variants in FSHB gene are associated with PCOS and LH levels in Han Chinese women. FSHB is thus likely to play an important role in the etiology of PCOS, regardless of ethnicity.

Replication of Han Chinese GWAS loci for schizophrenia via meta-analysis of four independent samples

Schizophrenia is a highly heritable psychiatric disorder with unclear aetiology. Recent genome-wide association studies (GWAS) in European populations have reported numerous susceptibility variants, while GWAS in East Asians also identified several risk loci but with fewer independent replications. Here we focus on nine single nucleotide polymorphisms (SNPs) which have shown genome-wide significant associations with schizophrenia in previous Han Chinese GWAS, and we tend to replicate the associations in four independent samples of East Asian origin including a total of 3977 cases and 5589 controls. The results showed that rs10489202 in MPC2 (BRP44) is significantly associated with schizophrenia in these East Asian replication samples (one-tailed P=5.75×10−3, OR=1.12), and further meta-analysis after including previous GWAS data yielded a genome-wide significant association (two-tailed P=1.11×10−10, OR=1.19), adding further support for the involvement of this locus in the genetic risk of schizophrenia, and future studies regarding the underlying molecular mechanisms of the risk association are necessary.

Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population.

Multiple risk variants of schizophrenia have been identified by Genome-wide association studies (GWAS). As a complement for GWAS, previous pathway-based analysis has indicated that cell adhesion molecules (CAMs) pathway might be involved in the pathogenesis of schizophrenia. However, less replication studies have been reported. Our objective was to investigate the association between CAMs pathway and schizophrenia in the Chinese Han population. We first performed a pathway analysis utilizing our previous GWAS data. The CAMs pathway (hsa04514) was significantly associated with schizophrenia using hybrid gene set-based test (P = 1.03×10−10) and hypergeometric test (P = 5.04×10−6). Moreover, 12 genes (HLA-A, HLA-C, HLA-DOB, HLA-DPB1, HLA-DQA2, HLA-DRB1, MPZ, CD276, NLGN1, NRCAM, CLDN1 and ICAM3) were modestly significantly associated with schizophrenia (P<0.01). Then, we selected one promising gene neuroligin 1 (NLGN1) to further investigate the association between eight significant SNPs and schizophrenia in an independent sample (1814 schizophrenia cases and 1487 healthy controls). Our study showed that seven SNPs of NLGN1 and two haplotype blocks were significantly associated with schizophrenia. This association was confirmed by the results of combined analysis. Among them, SNP rs9835385 had the most significant association with schizophrenia (P = 2.83×10−7). Furthermore, in silico analysis we demonstrated that NLGN1 is preferentially expressed in human brain and SNP rs1488547 was related to the expression level. We validated the association of CAMs pathway with schizophrenia in pathway-level and identified one susceptibility gene NLGN1. Further investigation of the roles of CAMs pathway in the pathogenesis of schizophrenia is warranted.

Four genetic variants interact to confer susceptibility to atopic dermatitis in Chinese Han population.

Atopic dermatitis is a chronic inflammatory skin disease and is affected by environmental and genetic factors. Gene-gene/environment interactions are strongly believed to contribute to the genetic risk of common diseases. A number of gene-environment interactions of atopic dermatitis were performed. However, there are few comprehensive investigations on the gene-gene (or genetic variants) interactions for atopic dermatitis. We explored the association model of 6 single nucleotide polymorphisms (SNPs) which were most significant (P < 10E-05) in our previous genome wide association study (GWAS) for atopic dermatitis, and search for the possible genetic variant interactions based on the previous GWAS data using Generalized Multifactor Dimensionality Reduction and Plink 1.07 in the combined sample of 4,636 cases and 13,559 controls. The most significant associated evidence was observed under dominant model for SNPs rs3126085, rs12085366, and rs7701890, recessive model for SNP rs17173197, and additive model for SNPs rs2393903 and rs6010620. Three significant pair-way interactions were observed, including PRKAG2 and FLG SNPs (rs17173197 × rs3126085, P combined = 1.11E-15), PRKAG2 and TMEM232-SLC25A46 SNPs (rs17173197 × rs7701890, P combined = 2.22E-15), PRKAG2 and TNFRSF6B-ZGPAT SNPs (rs17173197 × rs6010620, P combined = 6.66E-16). Besides, a three-way significant interaction among PRKAG2, TMEM232-SLC25A46 and TNFRSF6B-ZGPAT SNPs (rs17173197 × rs7701890 × rs6010620, P combined = 5.99E-15) was observed in this study. These four genetic variant interactions confer susceptibility to atopic dermatitis, and highlight the genetic variant interactions in the etiology of atopic dermatitis in Chinese Han population.

Protein-interaction-network-based analysis for genome-wide association analysis of schizophrenia in Han Chinese population

Schizophrenia is a severe neuropsychiatric disorder with a strong and complex genetic background. Recent genome-wide association studies (GWAS) have successfully identified several susceptibility loci of schizophrenia. In order to interpret the functional role of the genetic variants and detect the combined effects of some of these genes on schizophrenia, protein-interaction-network-based analysis (PINBA) has emerged as an effective approach. In the current study, we conducted a PINBA of our previous GWAS data taken from the Han Chinese population. In order to do so, we used dense module search (DMS), a method that locates densely connected modules for complex diseases by integrating the association signal from GWAS datasets into the human protein–protein interaction (PPI) network. As a result, we identified one gene set with a joint effect significantly associated with schizophrenia and gene expression profiling analysis suggested that they were mainly neuro- and immune-related genes, such as glutamatergic gene (GRM5), GABAergic genes (GABRB1, GABARAP) and genes located in the MHC region (HLA-C, TAP2, HIST1H1B). Further pathway enrichment analysis suggested that these genes are involved in processes related to neuronal and immune systems, such as the Adherens junction pathway, the Neurotrophin signaling pathway and the Toll-like receptor signaling pathway. In our study, we identified a set of susceptibility genes that had been missed in single-marker GWAS, and our findings could promote the study of the genetic mechanisms in schizophrenia.

Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis

Kawasaki disease (KD) is often complicated by coronary artery lesions (CALs), including aneurysms. Because of the complications associated with KD, this disorder is the leading cause of acquired heart disease in children from developed countries. To identify genetic loci that confer a higher risk of developing CALs, we performed a case-control association study using previous genome-wide association study data for samples from KD cases only (n=186) by grouping KD patients without CALs (control: n=123) vs KD patients with extremely large aneurysms (diameter>5 mm) (case: n=17). Twelve loci with one or more sequence variants were found to be significantly associated with CALs (P<1 × 10(-5)). Of these, an SNP (rs17136627) in the potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2 (KCNN2) at 5q22.3 was validated in 32 KD patients with large aneurysms (diameter>5 mm) and 191 KD patients without CALs (odds ratio (OR)=12.6, P(combined)=1.96 × 10(-8)). This result indicates that the KCNN2 gene can have an important role in the development of coronary artery aneurysms in KD.

Common Variants in CDKN2B-AS1 Associated with Optic-Nerve Vulnerability of Glaucoma Identified by Genome-Wide Association Studies in Japanese

BackgroundTo date, only a small portion of the genetic variation for primary open-angle glaucoma (POAG), the major type of glaucoma, has been elucidated.Methods and Principal FindingsWe examined our two data sets of the genome-wide association studies (GWAS) derived from a total of 2,219 Japanese subjects. First, we performed a GWAS by analyzing 653,519 autosomal common single-nucleotide polymorphisms (SNPs) in 833 POAG patients and 686 controls. As a result, five variants that passed the Bonferroni correction were identified in CDKN2B-AS1 on chromosome 9p21.3, which was already reported to be a significant locus in the Caucasian population. Moreover, we combined the data set with our previous GWAS data set derived from 411 POAG patients and 289 controls by the Mantel-Haenszel test, and all of the combined variants showed stronger association with POAG (P<5.8×10−10). We then subdivided the case groups into two subtypes based on the value of intraocular pressure (IOP)—POAG with high IOP (high pressure glaucoma, HPG) and that with normal IOP (normal pressure glaucoma, NPG)—and performed the GWAS using the two data sets, as the prevalence of NPG in Japanese is much higher than in Caucasians. The results suggested that the variants from the same CDKN2B-AS1 locus were likely to be significant for NPG patients.Conclusions and SignificanceIn this study, we successfully identified POAG-associated variants in the CDKN2B-AS1 locus using a Japanese population, i.e., variants originally reported as being associated with the Caucasian population. Although we cannot rule out that the significance could be due to the differences in sample size between HPG and NPG, the variants could be associated specifically with the vulnerability of the optic nerve to IOP, which is useful for investigating the etiology of glaucoma.

Genetic effects and modifiers of radiotherapy and chemotherapy on survival in pancreatic cancer.

Germ-line genetic variation may affect clinical outcomes of cancer patients. We applied a candidate-gene approach to evaluate the effect of putative markers on survival of patients with pancreatic cancer. We also examined gene-radiotherapy and gene-chemotherapy interactions, aiming to explain interindividual differences in treatment outcomes. In total, 211 patients with pancreatic cancer were recruited in a population-based study. Sixty-four candidate genes associated with cancer survival or treatment response were selected from existing publications. Genotype information was obtained from a previous genome-wide association study data set. The main effects of genetic variation and gene-specific treatment interactions on overall survival were examined by proportional hazards regression models. Fourteen genes showed evidence of association with pancreatic cancer survival. Among these, rs1760217, located at the DPYD gene; rs17091162 at SERPINA3; and rs2231164 at ABCG2 had the lowest P of 10(-4.60), 0.0013, and 0.0023, respectively. We also observed that 2 genes, RRM1 and IQGAP2, had significant interactions with radiotherapy in association with survival, and 2 others, TYMS and MET, showed evidence of interaction with 5-fluorouracil and erlotinib, respectively. Our study suggested significant associations between germ-line genetic polymorphisms and overall survival in pancreatic cancer, as well as survival interactions between various genes and radiotherapy and chemotherapy.