Mutation screening of EXT genes in Chinese patients with multiple osteochondromas

Since vascular risk factors commonly act for susceptibility to Alzheimer's disease (AD) and vascular dementia (VaD) by declining cognitive abilities, we conducted a genetic association study to identify their common underlying genetic factors. We selected single nucleotide polymorphisms (SNPs) which had been previously discovered for association with AD, and case and control associations of VaD were examined with the individual SNPs using 207 patients with VaD and 207 sex- and age-matched control subjects. As a result, no significant associations of susceptibility to VaD with 13 selected SNPs were observed even without employing a multiple test (P>0.05). This study suggests that genetics of VaD might be quite different from that of AD, and cautions should be taken especially when inferences about genetic factors are made with patients with mixed dementia.     

Genetic variations in VDR associated with prostate cancer risk and progression in a Korean population

Low levels of vitamin D are implicated as a potential risk factor for prostate cancer, and the vitamin D receptor (VDR) gene may be important in the onset and progression of prostate cancer. In this study, sequence variants in the VDR gene were investigated in a Korean study cohort to determine whether they are associated with prostate cancer risk. We evaluated the association between 47 single nucleotide polymorphisms (SNPs) in the VDR gene and prostate cancer risk as well as clinical characteristics (prostate-specific antigen level, clinical stage, pathological stage and Gleason score) in Korean men (272 prostate cancer patients and 173 benign prostatic hyperplasia patient who underwent a prostate biopsy, which was negative for malignancy) using unconditional logistic regression. The statistical analysis suggested that two VDR sequence variants (rs2408876 and rs2239182) had a significant association with prostate cancer risk (odds ratio [OR]. 1.41; p = 0.03; OR, 0.73; p = 0.05, respectively). Logistic analyses of the VDR polymorphisms with several prostate cancer related factors showed that several SNPs were significant; nine SNPs to PSA level, three to clinical stage, two to pathological stage, and three SNPs to the Gleason score. The results suggest that some VDR gene polymorphisms in Korean men might not only be associated with prostate cancer risk but also significantly related to prostate cancer-related risk factors such as PSA level, tumor stage, and Gleason score. However, current limitation for small cohort with not-healthy control group might have false positive effects; therefore it should be overcome via further large-scale validating studies.     

遗传风险评分在复杂疾病遗传学研究中的应用

心血管疾病、2型糖尿病、原发性高血压、哮喘、肥胖、肿瘤等复杂疾病在全球范围内流行,并成为人类死亡的主要原因。越来越多的人开始关注遗传易感性在复杂疾病发病机制中的作用。至今,与复杂疾病相关的易感基因和基因序列变异仍未完全清楚。人们希望通过遗传关联研究来阐明复杂疾病的遗传基础。近年来,全基因组关联研究和候选基因研究发现了大量与复杂疾病有关的基因序列变异。这些与复杂疾病有因果和(或)关联关系的基因序列变异的发现促进了复杂疾病预测和防治方法的产生和发展。遗传风险评分(Genetic risk score,GRS)作为探索单核苷酸多态(Single nucleotide polymorphisms,SNPs)与复杂疾病临床表型之间关系的新兴方法,综合了若干SNPs的微弱效应,使基因多态对疾病的预测性大幅度提升。该方法在许多复杂疾病遗传学研究中得到成功应用。本文重点介绍了GRS的计算方法和评价标准,简要列举了运用GRS取得的系列成果,并对运用过程中所存在的局限性进行了探讨,最后对遗传风险评分的未来发展方向进行了展望。     

Association between the C.1161G>A and C.1779C>G Genetic Variants of XRCC1 Gene and Hepatocellular Carcinoma Risk in Chinese Population

The human X-ray repair complementing group 1 gene (XRCC1) is an important candidate gene influencing hepatocellular carcinoma (HCC) susceptibility. The objective of this study was to detect the association between c.1161G>A and c.1779C>G variants of XRCC1 gene and HCC risk. This study was conducted in Chinese population consisting of 623 HCC cases and 639 controls. These two genetic variants could be genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association of XRCC1 gene variants with the risk of HCC was investigated under different genetic models. Our findings suggested that the genotypes/alleles from c.1161G>A and c.1779C>G genetic variants were statistically associated with HCC risk. As for the c.1161G>A, the AA genotype was statistically associated with the increased risk of HCC compared to GG wild genotype (OR = 2.36, 95% CI 1.63-3.40, P < 0.001). As for the c.1779C>G, the risk of HCC was significantly higher for GG genotype compared to CC wild genotype (OR = 2.17, 95% CI 1.51-3.12, P < 0.001). Furthermore, significant differences in the risk of HCC were also detected in other genetic models for these two variants. The allele-A of c.1161G>A and allele-G of c.1779C>G variants may contribute to the susceptibility of HCC (A versus G: OR = 1.48, 95% CI 1.26-1.75, P < 0.001 and G versus C: OR = 1.51, 95% CI 1.28-1.78, P < 0.001). Our data indicated that these two variants of XRCC1 gene were statistically associated with HCC risk in Chinese population.     

Genome-wide association study reveals five nucleotide sequence variants for carcass traits in beef cattle

Genetic associations of nucleotide sequence variants with carcass traits in beef cattle were investigated using a genome-wide single nucleotide polymorphism (SNP) assay. Three hundred and thirteen Korean cattle were genotyped with the Illumina BovineSNP50 BeadChip, and 39,129 SNPs from 311 animals were analysed for each carcass phenotype after filtering by quality assurance. Five sequence markers were associated with one of the meat quantity or quality traits; rs109593638 on chromosome 3 with marbling score, rs109821175 on chromosome 11 and rs110862496 on chromosome 13 with backfat thickness (BFT), and rs110228023 on chromosome 6 and rs110201414 on chromosome 16 with eye muscle area (EMA) (P < 1.27 × 10(-6) , Bonferonni P < 0.05). The ss96319521 SNP, located within a gene with functions of muscle development, dishevelled homolog 1 (DVL1), would be a desirable candidate marker. Individuals with genotype CC at this gene appeared to have increased both EMA and carcass weight. Fine-mapping would be required to refine each of the five association signals shown in the current study for future application in marker-assisted selection for genetic improvement of beef quality and quantity.     

Association between the g.296596G > A genetic variant of RELN gene and susceptibility to autism in a Chinese Han population

Autism is a childhood neuro-developmental disorder, and Reelin (RELN) is an important candidate gene for influencing autism. This study aimed at investigating the influence of genetic variants of the RELN gene on autism susceptibility. In this study, 205 autism patients and 210 healthy controls were recruited and the genetic variants of the RELN gene were genotyped by the created restriction site-polymerase chain reaction (CRS-PCR) method. The influence of genetic variants on autism susceptibility was analyzed by association analysis, and the g.296596G > A genetic variant in exon10 of the RELN gene was detected. The frequencies of allele/genotype in autistic patients were significantly different from those in healthy controls, and a statistically significant association was detected between this genetic variant and autism susceptibility. Our data lead to the inference that the g.296596G > A genetic variant in the RELN gene has a potential influence on autism susceptibility in the Chinese Han population.     

A genome-wide association analysis reveals 1p31 and 2p13.3 as susceptibility loci for Kawasaki disease

Kawasaki disease (KD) is an acute self-limited vasculitis of infants and children that manifests as fever and signs of mucocutaneous inflammation. Coronary artery aneurysms develop in approximately 15-25% of untreated children. Although the etiology of KD is largely unknown, epidemiologic data suggest the importance of genetic factors in the susceptibility to KD. In order to identify genetic variants that influence KD susceptibility, we performed a genome-wide association study (GWAS) using Affymetrix SNP array 6.0 in 186 Korean KD patients and 600 healthy controls; 18 and 26 genomic regions with one or more sequence variants were associated with KD and KD with coronary artery lesions (CALs), respectively (p?相似文献   

Genetic association of marbling score with intragenic nucleotide variants at selection signals of the bovine genome

Selection signals of Korean cattle might be attributed largely to artificial selection for meat quality. Rapidly increased intragenic markers of newly annotated genes in the bovine genome would help overcome limited findings of genetic markers associated with meat quality at the selection signals in a previous study. The present study examined genetic associations of marbling score (MS) with intragenic nucleotide variants at selection signals of Korean cattle. A total of 39 092 nucleotide variants of 407 Korean cattle were utilized in the association analysis. A total of 129 variants were selected within newly annotated genes in the bovine genome. Their genetic associations were analyzed using the mixed model with random polygenic effects based on identical-by-state genetic relationships among animals in order to control for spurious associations produced by population structure. Genetic associations of MS were found (P<3.88×10⁻⁴) with six intragenic nucleotide variants on bovine autosomes 3 (cache domain containing 1, CACHD1), 5 (like-glycosyltransferase, LARGE), 16 (cell division cycle 42 binding protein kinase alpha, CDC42BPA) and 21 (snurportin 1, SNUPN; protein tyrosine phosphatase, non-receptor type 9, PTPN9; chondroitin sulfate proteoglycan 4, CSPG4). In particular, the genetic associations with CDC42BPA and LARGE were confirmed using an independent data set of Korean cattle. The results implied that allele frequencies of functional variants and their proximity variants have been augmented by directional selection for greater MS and remain selection signals in the bovine genome. Further studies of fine mapping would be useful to incorporate favorable alleles in marker-assisted selection for MS of Korean cattle.     

Heterogeneous genetic associations of nucleotide sequence variants with bone mineral density by gender

We examined genetic associations of previously identified sequence variants with bone mineral density and their heterogeneity by gender. Large-scale cohort data were used including a total of 8,419 subjects (4,034 males and 4,385 females) from the Korean Association REsource (KARE) cohort. Bone speed of sound (SOS) values were measured at distal radius or mid-shaft tibia by quantitative ultrasound. Genotypic associations of SOS were tested with each of nucleotide sequence variants identified by previous studies. The genetic association analysis revealed that 2 out of 11 nucleotide sequence variants were associated with SOS (rs1721400, rs7776725, P < 7.58 × 10⁻⁴). Further analysis with partitioning data by gender showed that the mid-shaft tibia phenotypes were associated with the rs1721400 and rs7776725 in females (P < 3.79 × 10⁻⁴), but not in males (P > 3.79 × 10⁻⁴). The current study suggested female-specific associations of rs1721400 and rs7776725 with bone mineral density and heterogeneity of genetic association by skeletal site measured for bone mineral density.     

Analysis of the DISC1 translocation partner (11q14.3) in genetic risk of schizophrenia

The Disrupted‐in‐Schizophrenia 1 (DISC1) locus on human chromosome 1 was identified as a consequence of its involvement in a balanced translocation (1;11)(q42.1;q14.3) segregating with major psychiatric disorders in a Scottish family. Recently a comprehensive meta‐analysis of genome‐wide association scan data found no evidence that common variants of DISC1 (1q42.1) are associated with schizophrenia. Our aim was to test for association of variants in the 11q14.3 translocation region with schizophrenia. The 11q14.3 region was examined by meta‐analysis of genome‐wide scan data made available by the Genetic Association Information Network (GAIN) and other investigators (non‐GAIN) through dbGap. P‐values were adjusted for multiple testing using the false discovery rate (FDR) approach. There were no single‐nucleotide polymorphisms (SNPs) significant (P < 0.05) after correction for multiple testing in the combined schizophrenia dataset. However, one SNP (rs2509382) was significantly associated in the male‐only analysis with P_FDR = 0.024. Whilst the relevance of the (1;11)(q42.1;q14.3) translocation to psychiatric disorders is currently specific to the Scottish family, genetic material in the chromosome 11 region may contain risk variants for psychiatric disorders in the wider population. The association found in this region does warrant follow‐up analysis in further sample sets .     

Effects of cis and trans regulatory variations on the expression divergence of heat shock response genes between yeast strains

Recently, two genome-wide association studies in Asia identified gene polymorphisms known as rs4488809, rs9816619 in TP63 and rs2131877, rs952481 in C3orf21. It has been proposed that these polymorphisms are susceptibility loci for non-small cell lung cancer (NSCLC) development among Japanese and Korean populations. We ask whether susceptibility to NSCLC is limited to the Chinese population or whether the environment also affects genetic polymorphisms. We conducted a matched case-control study to explore this question. Results show that polymorphism of TP63 was not associated with NSCLC development, whereas variant genotypes of C3orf21 were nominally associated with a reduced risk of lung adenocarcinoma (OR=0.619, 95% CI=0.390-0.976). These results strongly suggest that environmental agents interact with human genetic polymorphism independent of ethnic background. In addition, the C3orf21 gene may be a potential susceptibility marker for lung adenocarcinoma independent of ethnic background and environmental agents.     

Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women

Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.     

Association Study of Single Nucleotide Polymorphisms in XRCC1 Gene with the Risk of Gastric Cancer in Chinese Population

Gastric cancer is one of highly cancer-related deaths in the world. Previous evidence suggests that the X-ray repair cross-complementing group 1 gene (XRCC1) is one of the most important candidate genes for influencing gastric cancer risk. The objective of this study was to detect the potential association of genetic variants in XRCC1 gene with gastric cancer risk in Chinese Han population. In total, we enrolled 395 gastric cancer patients and 398 cancer-free controls in this study. The genotyping of c.910A>G and c.1804C>A genetic variants in XRCC1 gene were investigate by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and created restriction site-PCR (CRS-PCR) methods, respectively. We found the genotypes/alleles from these two genetic variants were statistically associated with the increased risk of gastric cancer (for c.910A>G, GG versus (vs.) AA: OR = 2.00, 95% CI 1.21-3.31; AG vs. AA: OR = 1.50, 95% CI 1.12-2.02; GG/AG vs. AA: OR = 1.59, 95% CI 1.20-2.10; GG vs. AG/AA: OR = 1.68, 95% CI 1.03-2.73; G vs. A: OR = 1.47, 95% CI 1.18-1.83; for c.1804C>A, AA vs. CC: OR = 2.68, 95% CI 1.46-4.94; AA vs. CA/CC: OR = 2.62, 95% CI 1.44-4.76; A vs. C: OR = 1.33, 95% CI 1.06-1.66). The allele-G of c.910A>G and allele-A of c.1804C>A genetic variants may contribute to gastric cancer susceptibility. These preliminary results indicate that these XRCC1 genetic variants are potentially related to gastric cancer susceptibility in Chinese Han population, and might be used as molecular markers.     

Allelic variants of DYX1C1 are not associated with dyslexia in India

Dyslexia is a hereditary neurological disorder that manifests as an unexpected difficulty in learning to read despite adequate intelligence, education, and normal senses. The prevalence of dyslexia ranges from 3 to 15% of the school aged children. Many genetic studies indicated that loci on 6p21.3, 15q15-21, and 18p11.2 have been identified as promising candidate gene regions for dyslexia. Recently, it has been suggested that allelic variants of gene, DYX1C1 influence dyslexia. In the present study, exon 2 and 10 of DYX1C1 has been analyzed to verify whether these single nucleotide polymorphisms (SNPs) influence dyslexia, in our population. Our study identified 4 SNPs however, none of these SNPS were found to be significantly associated with dyslexia suggesting DYX1C1 allelic variants are not associated with dyslexia.     

Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript

Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P?=?3.9?×?10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P?=?1.9?×?10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.     

Identifying disease related sub-pathways for analysis of genome-wide association studies

Most methods for genome-wide association studies (GWAS) focus on discovering a single genetic variant, but the pathogenesis of complex diseases is thought to arise from the joint effect of multiple genetic variants. Information about pathway structure, such as the interactions and distances between gene products within pathways, can help us learn more about the functions and joint effect of genes associated with disease risk. We developed a novel sub-pathway based approach to study the joint effect of multiple genetic variants that are modestly associated with disease. The approach prioritized sub-pathways based on the significance values of single nucleotide polymorphisms (SNPs) and the interactions and distances between gene products within pathways. We applied the method to seven complex diseases. The result showed that our method can efficiently identify statistically significant sub-pathways associated with the pathogenesis of complex diseases. The approach identified sub-pathways that may inform the interpretation of GWAS data.     

Polymorphic allele of human MRC1 confer protection against tuberculosis in a Chinese population

Mannose receptor is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition, and plays a critical role in shaping host immune response. Single nucleotide polymorphisms (SNPs) in the MRC1 gene may affect expression levels and differences in the structure and function of proteins in different individuals, thereby affecting individual susceptibility to pulmonary tuberculosis. However, to date, MRC1 polymorphisms associated with susceptibility to pulmonary tuberculosis have not yet been reported. The present study aimed to investigate potential associations of SNPs in the MRC1 gene with pulmonary tuberculosis in a Chinese population. Six SNPs (G1186A, G1195A, T1212C, C1221G, C1303T and C1323T) in exon 7 of the MRC1 gene were genotyped using the PCR and DNA sequencing methods in the pulmonary tuberculosis patients and the healthy controls. Linkage disequilibrium analysis was performed between polymorphic sites. The study found that the allele frequency of G1186A (rs34039386) of the MRC1 gene in a Chinese population was higher in the pulmonary tuberculosis group than the healthy control group. There was a significant difference in frequency distribution between the two groups (P = 0.037; OR = 0.76; 95% CI, 0.58-0.98). Genotypic analysis also indicated that the AG genotypes in a Chinese population were significantly correlated with pulmonary tuberculosis (P < 0.01; OR = 0.57; 95% CI, 0.37-0.87). After adjustment for age and gender, G1186A sites were found to be dominant (P < 0.01; OR = 0.59; 95% CI, 0.40-0.87), over-dominant (P = 0.045; OR = 0.69; 95% CI, 0.47-0.99) and additive models (P = 0.041; OR = 0.76; 95% CI, 0.59-0.99) in association with pulmonary tuberculosis. But, no association was found between the other 5 SNPs (G1195A, T1212C, C1221G, C1303T and C1323T) and tuberculosis (P > 0.05). This study is the first to report that genetic variants in the MRC1 gene can be associated with pulmonary tuberculosis in a Chinese population, and may reduce the risk of infecting pulmonary tuberculosis. This also provides a new experimental basis to clarify the pathogenesis of pulmonary tuberculosis.     

Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population

Aspirin-exacerbated respiratory disease (AERD) is a nonallergic clinical syndrome characterized by a severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. The effects of genetic variants have not fully explained all of the observed individual differences to an aspirin challenge despite previous attempts to identify AERD-related genes. In the present study, we performed genome-wide association study (GWAS) and targeted association study in Korean asthmatics to identify new genetic factors associated with AERD. A total of 685 asthmatic patients without AERD and 117 subjects with AERD were used for the GWAS of the first stage, and 996 asthmatics without AERD and 142 subjects with AERD were used for a follow-up study. A total of 702 SNPs were genotyped using the GoldenGate assay with the VeraCode microbead. GWAS revealed the top-ranked variants in 3′ regions of the HLA-DPB1 gene. To investigate the detailed genetic effects of an associated region with the risk of AERD, a follow-up targeted association study with the 702 single nucleotide polymorphisms (SNPs) of 14 genes was performed on 802 Korean subjects. In a case–control analysis, HLA-DPB1 rs1042151 (Met105Val) shows the most significant association with the susceptibility of AERD (p = 5.11 × 10^?7; OR = 2.40). Moreover, rs1042151 also shows a gene dose for the percent decline of FEV1 after an aspirin challenge (p = 2.82 × 10^?7). Our findings show that the HLA-DPB1 gene polymorphism may be the most susceptible genetic factor for the risk of AERD in Korean asthmatics and confirm the importance of HLA-DPB1 in the genetic etiology of AERD.     

Identification of contemporary selection signatures using composite log likelihood and their associations with marbling score in Korean cattle

Positive selection not only increases beneficial allele frequency but also causes augmentation of allele frequencies of sequence variants in close proximity. Signals for positive selection were detected by the statistical differences in subsequent allele frequencies. To identify selection signatures in Korean cattle, we applied a composite log‐likelihood (CLL)‐based method, which calculates a composite likelihood of the allelic frequencies observed across sliding windows of five adjacent loci and compares the value with the critical statistic estimated by 50 000 permutations. Data for a total of 11 799 nucleotide polymorphisms were used with 71 Korean cattle and 209 foreign beef cattle. As a result, 147 signals were identified for Korean cattle based on CLL estimates (P < 0.01). The signals might be candidate genetic factors for meat quality by which the Korean cattle have been selected. Further genetic association analysis with 41 intragenic variants in the selection signatures with the greatest CLL for each chromosome revealed that marbling score was associated with five variants. Intensive association studies with all the selection signatures identified in this study are required to exclude signals associated with other phenotypes or signals falsely detected and thus to identify genetic markers for meat quality.