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Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a Chinese Han Population  [PDF]
Li Zhou, Hu Ding, Xiaomin Zhang, Meian He, Suli Huang, Yujun Xu, Ying Shi, Guanglin Cui, Longxian Cheng, Qing K. Wang, Frank B. Hu, Daowen Wang, Tangchun Wu
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027481
Abstract: Background Recent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population. Methodology/Principal Findings We conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10?8), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10?4 and 0.001, respectively). Conclusions/Significance We identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population.
Replication of Putative Susceptibility Loci from Genome-Wide Association Studies Associated with Coronary Atherosclerosis in Chinese Han Population  [PDF]
Fang Xie,Xun Chu,Hong Wu,Weiwei Sun,Min Shen,Lin Yang,Ying Wang,Yi Wang,Jinxiu Shi,Wei Huang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020833
Abstract: Coronary atherosclerosis, the main cause of cardiovascular disease, is a progressive disease. Recent Genome Wide Association Studies (GWASs) discovered several novel loci associated with coronary artery disease (CAD) or its main complication myocardial infarction (MI). In this study, we investigated the associations between previously reported CAD- and MI-associated variants and coronary atherosclerosis in Chinese Han population.
A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese  [PDF]
Fuu-Jen Tsai equal contributor,Chi-Fan Yang equal contributor,Ching-Chu Chen equal contributor,Lee-Ming Chuang,Chieh-Hsiang Lu,Chwen-Tzuei Chang,Tzu-Yuan Wang,Rong-Hsing Chen,Chiung-Fang Shiu,Yi-Min Liu,Chih-Chun Chang,Pei Chen,Chien-Hsiun Chen,Cathy S. J. Fann,Yuan-Tsong Chen ,Jer-Yuarn Wu
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000847
Abstract: To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10?10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10?9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10?10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.
Cross-Sectional and Longitudinal Replication Analyses of Genome-Wide Association Loci of Type 2 Diabetes in Han Chinese  [PDF]
Qi Zhao, Jianzhong Xiao, Jiang He, Xuelian Zhang, Jing Hong, Xiaomu Kong, Katherine T. Mills, Jianping Weng, Weiping Jia, Wenying Yang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091790
Abstract: This study aimed to examine genomic loci of type 2 diabetes (T2D) initially identified by genome-wide association studies in populations of European ancestry for their associations with T2D and quantitative glycemic traits, as well as their effects on longitudinal change in fasting plasma glucose (FPG) and T2D development, in the Chinese population. Single nucleotide polymorphisms (SNP) from 25 loci were genotyped in a large case-control sample of 10,001 subjects (5,338 T2D cases and 4,663 controls) and a prospective cohort of 1,881 Chinese. In the case-control sample, 8 SNPs in or near WFS1, CDKAL1, CDKN2A/2B, CDC123, HHEX, TCF7L2, KCNQ1, and MTNR1B were significantly associated with T2D (P<0.05). Thirteen SNPs were associated with quantitative glycemic traits. For example, the most significant SNP, rs10811661 near CDKN2A/2B (P = 1.11×10?8 for T2D), was also associated with 2-h glucose level of an oral glucose tolerance test (P = 9.11×10?3) and insulinogenic index (P = 2.71×10?2). In the cohort study, individuals carrying more risk alleles of the replicated SNPs had greater FPG increase and T2D incidence in a 7.5-year follow-up period, with each quartile increase in the number of risk alleles being associated with a 0.06 mmol/l greater increase in FPG (P = 0.03) and 19% higher odds of developing T2D (P = 0.058). Our study identified the associations of several established T2D-loci in Europeans with T2D and quantitative glycemic traits in the Chinese population. The prospective data also suggest their potential role in the risk prediction of T2D in the Chinese population.
Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome
Thomas M Morgan, John A House, Sharon Cresci, Philip Jones, Hooman Allayee, Stanley L Hazen, Yesha Patel, Riyaz S Patel, Danny J Eapen, Salina P Waddy, Arshed A Quyyumi, Marcus E Kleber, Winfried M?rz, Bernhard R Winkelmann, Bernhard O Boehm, Harlan M Krumholz, John A Spertus
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-127
Abstract: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.Genome-wide association studies (GWAS) have identified robust genetic associations in a variety of common diseases [1], including myocardial infarction (MI) [2-6]. The GWAS approach, with its emphasis on large sample sizes and inclusion of hundreds of thousands of genetic markers, has produced a degree of reproducibility that was generally lacking in earlier candidate gene studies of MI [7]. However, nine GWAS-identified genetic susceptibility markers, all meeting criteria for genome-wide statistical significance, collectively account for only 3% of the estimated heritability of early-onset myocardial infarction (MI), raising questions about t
Genome-Wide Association Study Identified Copy Number Variants Important for Appendicular Lean Mass  [PDF]
Shu Ran, Yong-Jun Liu, Lei Zhang, Yufang Pei, Tie-Lin Yang, Rong Hai, Ying-Ying Han, Yong Lin, Qing Tian, Hong-Wen Deng
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089776
Abstract: Skeletal muscle is a major component of the human body. Age-related loss of muscle mass and function contributes to some public health problems such as sarcopenia and osteoporosis. Skeletal muscle, mainly composed of appendicular lean mass (ALM), is a heritable trait. Copy number variation (CNV) is a common type of human genome variant which may play an important role in the etiology of many human diseases. In this study, we performed genome-wide association analyses of CNV for ALM in 2,286 Caucasian subjects. We then replicated the major findings in 1,627 Chinese subjects. Two CNVs, CNV1191 and CNV2580, were detected to be associated with ALM (p = 2.26×10?2 and 3.34×10?3, respectively). In the Chinese replication sample, the two CNVs achieved p-values of 3.26×10?2 and 0.107, respectively. CNV1191 covers a gene, GTPase of the immunity-associated protein family (GIMAP1), which is important for skeletal muscle cell survival/death in humans. CNV2580 is located in the Serine hydrolase-like protein (SERHL) gene, which plays an important role in normal peroxisome function and skeletal muscle growth in response to mechanical stimuli. In summary, our study suggested two novel CNVs and the related genes that may contribute to variation in ALM.
Evaluating Genome-Wide Association Study-Identified Breast Cancer Risk Variants in African-American Women  [PDF]
Jirong Long, Ben Zhang, Lisa B. Signorello, Qiuyin Cai, Sandra Deming-Halverson, Martha J. Shrubsole, Maureen Sanderson, Joe Dennis, Kyriaki Michailiou, Douglas F. Easton, Xiao-Ou Shu, William J. Blot, Wei Zheng
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058350
Abstract: Genome-wide association studies (GWAS), conducted mostly in European or Asian descendants, have identified approximately 67 genetic susceptibility loci for breast cancer. Given the large differences in genetic architecture between the African-ancestry genome and genomes of Asians and Europeans, it is important to investigate these loci in African-ancestry populations. We evaluated index SNPs in all 67 breast cancer susceptibility loci identified to date in our study including up to 3,300 African-American women (1,231 cases and 2,069 controls), recruited in the Southern Community Cohort Study (SCCS) and the Nashville Breast Health Study (NBHS). Seven SNPs were statistically significant (P≤0.05) with the risk of overall breast cancer in the same direction as previously reported: rs10069690 (5p15/TERT), rs999737 (14q24/RAD51L1), rs13387042 (2q35/TNP1), rs1219648 (10q26/FGFR2), rs8170 (19p13/BABAM1), rs17817449 (16q12/FTO), and rs13329835 (16q23/DYL2). A marginally significant association (P<0.10) was found for three additional SNPs: rs1045485 (2q33/CASP8), rs4849887 (2q14/INHBB), and rs4808801 (19p13/ELL). Three additional SNPs, including rs1011970 (9p21/CDKN2A/2B), rs941764 (14q32/CCDC88C), and rs17529111 (6q14/FAM46A), showed a significant association in analyses conducted by breast cancer subtype. The risk of breast cancer was elevated with an increasing number of risk variants, as measured by quintile of the genetic risk score, from 1.00 (reference), to 1.75 (1.30–2.37), 1.56 (1.15–2.11), 2.02 (1.50–2.74) and 2.63 (1.96–3.52), respectively, (P = 7.8×10–10). Results from this study highlight the need for large genetic studies in AAs to identify risk variants impacting this population.
Characterization of Genome-Wide Association-Identified Variants for Atrial Fibrillation in African Americans  [PDF]
Jessica T. Delaney, Janina M. Jeff, Nancy J. Brown, Mias Pretorius, Henry E. Okafor, Dawood Darbar, Dan M. Roden, Dana C. Crawford
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032338
Abstract: Background Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown. Methodology/Principal Findings We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r2<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13–0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59–7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46–45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls. Conclusions/Significance Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations.
Meta-Analysis Indicates That the European GWAS-Identified Risk SNP rs1344706 within ZNF804A Is Not Associated with Schizophrenia in Han Chinese Population  [PDF]
Ming Li, Hui Zhang, Xiong-jian Luo, Lei Gao, Xue-bin Qi, Pierre-Antoine Gourraud, Bing Su
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065780
Abstract: Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizophrenia in Europeans through genome-wide association studies (GWASs) and replications as well as large-scale meta-analyses. However, in Han Chinese, the results for rs1344706 are inconsistent, and whether rs1344706 is an authentic risk SNP for schizophrenia in Han Chinese is inconclusive. Here, we conducted a systematic meta-analysis of rs1344706 with schizophrenia in Chinese population by combining all available case-control samples (N = 12), including a total of 8,982 cases and 12,342 controls. The results of our meta-analysis were not able to confirm an association of rs1344706 A-allele with schizophrenia (p = 0.10, odds ratio = 1.06, 95% confidence interval = 0.99–1.13). Such absence of association was further confirmed by the non-superiority test (p = 0.0003), suggesting that rs1344706 is not a risk SNP for schizophrenia in Han Chinese. Detailed examinations of individual samples revealed potential sampling bias in previous replication studies in Han Chinese. The absence of rs1344706 association in Han Chinese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating genome-wide association findings of schizophrenia across different ethnic populations.
New Sequence Variants in HLA Class II/III Region Associated with Susceptibility to Knee Osteoarthritis Identified by Genome-Wide Association Study  [PDF]
Masahiro Nakajima,Atsushi Takahashi,Ikuyo Kou,Cristina Rodriguez-Fontenla,Juan J. Gomez-Reino,Tatsuya Furuichi,Jin Dai,Akihiro Sudo,Atsumasa Uchida,Naoshi Fukui,Michiaki Kubo,Naoyuki Kamatani,Tatsuhiko Tsunoda,Konstantinos N. Malizos,Aspasia Tsezou,Antonio Gonzalez,Yusuke Nakamura,Shiro Ikegawa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009723
Abstract: Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of ~4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43×10?8 for rs7775228 and 6.73×10?8 for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA.
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