Yu X.-Q.,Sun Yat Sen University |
Yu X.-Q.,Key Laboratory of Nephrology |
Li M.,Sun Yat Sen University |
Li M.,Key Laboratory of Nephrology |
And 32 more authors.
Nature Genetics | Year: 2012
We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10 -11, OR = 1.21; rs4227, P = 4.31 × 10 -10, OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10 -14, OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10-20, OR = 1.34; rs1794275, P = 3.43 × 10 -13, OR = 1.30; rs2523946, P = 1.74 × 10 -11, OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10 -11, OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation. © 2012 Nature America, Inc. All rights reserved.
Coin L.J.M.,BGI Shenzhen |
Coin L.J.M.,Imperial College London |
Cao D.,BGI Shenzhen |
Ren J.,BGI Shenzhen |
And 14 more authors.
Bioinformatics | Year: 2012
Motivation: Despite the prevalence of copy number variation (CNV) in the human genome, only a handful of confirmed associations have been reported between common CNVs and complex disease. This may be partially attributed to the difficulty in accurately genotyping CNVs in large cohorts using array-based technologies. Exome sequencing is now widely being applied to case-control cohorts and presents an exciting opportunity to look for common CNVs associated with disease. Results: We developed ExoCNVTest: an exome sequencing analysis pipeline to identify disease-associated CNVs and to generate absolute copy number genotypes at putatively associated loci. Our method re-discovered the LCE3B_LCE3C CNV association with psoriasis (P-value = 5 × 10e-6) while controlling inflation of test statistics (λ<1). ExoCNVTest-derived absolute CNV genotypes were 97.4% concordant with PCR-derived genotypes at this locus. © The Author(s) 2012. Published by Oxford University Press.
Zha X.,Peking Union Medical College |
Zha X.,Anhui Medical University |
Zha X.,State Key Laboratory Incubation Base of Dermatology |
Hu Z.,Peking Union Medical College |
And 4 more authors.
Cancer Letters | Year: 2011
Aberrant activation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss or inactivation of TSC1/TSC2 protein complex, leads to negative feedback inhibition of Akt. The exact mechanisms of this process are still not fully understood. Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process. We demonstrate that STAT3 promotes the transcription of PTEN by directly binding on the PTEN promoter. Elevated PTEN then inhibits the proliferation of Tsc1 -/- or Tsc2 -/- cells through down-regulation of Akt signaling. Activation of PTEN in this pathway may thus serve as a protective mechanism against hyper-activated mTORC1 mediated tumorigenesis and contribute to the benign nature of tumors caused by loss of either TSC1 or TSC2. © 2011 Elsevier Ireland Ltd.
Barzan D.,University of Heidelberg |
Barzan D.,Hannover Medical School |
Veldwijk M.R.,University of Heidelberg |
Herskind C.,University of Heidelberg |
And 9 more authors.
European Journal of Human Genetics | Year: 2013
Genome-wide association studies (GWAS) identified several genetic risk factors for breast cancer, however, most of them were validated among women of European ancestry. This study examined single-nucleotide polymorphisms (SNPs) contributing to breast cancer in Chinese (984 cases and 2206 controls) and German (311 cases and 960 controls) populations. Eighteen SNPs significantly associated with breast cancer, previously identified in GWAS were genotyped. Twelve SNPs passed quality control and were subjected to statistical analysis. Seven SNPs were confirmed to be significantly associated with breast cancer in the Chinese population, reflecting three independent loci (ESR1, FGFR2, TOX3) and five of these were also confirmed in the German population. The strongest association was identified for rs2046210 in the Chinese (odds ratio (OR)=1.42, 95% confidence interval (CI)=1.28-1.59, P=1.9 × 10-10) and rs3803662 in the German population (OR=1.43, 95% CI=1.17-1.74, P=4.01 × 10-4), located upstream of the ESR1 and TOX3 gene, respectively. For the first time, rs3757318 at 6q25.1, located next to the gene encoding estrogen receptor α (ESR1) was found to be strongly associated with breast cancer (OR=1.33, 95% CI=1.18-1.49, P=1.94 × 10-6) in the Chinese population. The frequency of this variant was markedly lower in the German population and the association was not significant. Despite the genetic differences, essentially the same risk loci were identified in the Chinese and the German populations. Our study suggested the existence of common genetic factors as well as disease susceptibility differences for breast cancer in both populations and highlighted the importance of performing comparison analyses for disease susceptibility within ethnic populations. © 2013 Macmillan Publishers Limited.
Liu J.L.,Hainan Nongken General Hospital |
Zhang S.Q.,Anhui Medical University |
Zhang S.Q.,State Key Laboratory Incubation Base of Dermatology |
Zeng H.M.,Affiliated Hospital
Journal of the European Academy of Dermatology and Venereology | Year: 2013
Objectives To determine whether ApaI, BsmI, FokI or TaqI polymorphisms in vitamin D receptor (VDR) gene confer susceptibility to psoriasis. Methods All related association studies published before January 2012 were retrieved and eligible ones were included in our meta-analysis. For each of the four polymorphisms, we explored the significance of the associations for the allele contrast as well as the recessive and dominant models in overall samples, Caucasians and East Asians. Heterogeneity was identified by sensitivity analysis and publication bias was examined by funnel plot and Egger's test. Results 12 studies that met our selection criteria were included. For ApaI polymorphism, the dominant model for allele a in Caucasians produced a significant result [heterogeneity χ2=3.46, P = 0.177, I2=42.2%; OR fixed-effect model = 1.398 (1.011-1.934), z = 2.03, P = 0.043]. While in East Asians, pooling analysis under any genetic model acquired no-significant result. Significant heterogeneity was identified among East Asian studies and a Korean study accounted mostly for the heterogeneity detected. The heterogeneities were no longer statistically significant after removing this study, and the results of re-analyses in remaining studies have not been affected. Regarding TaqI polymorphism, the allele contrast discovered significant association between allele T and psoriasis susceptibility in Caucasians [heterogeneity χ2 = 4.35, P = 0.226, I2 = 31.1%; ORfixed-effect model = 1.287 (1.067-1.551), z = 2.64, P = 0.008]. As for the BsmI and FokI polymorphisms, allele contrast, recessive and dominant models produced non-significant results in either Caucasians or East Asians. The funnel plots and Egger's tests found no publication bias presenting in the studies analyzed. Conclusions This meta-analysis showed that ApaI, TaqI polymorphisms in VDR gene correlate with psoriasis in Caucasians. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.
PubMed | Sun Yat Sen University, Johns Hopkins University, Central South University, Yale University and 4 more.
Type: Journal Article | Journal: Molecular psychiatry | Year: 2014
Autism is a highly heritable neurodevelopmental disorder, and known genetic variants, mostly rare, account only for a small proportion of cases. Here we report a genome-wide association study on autism using two Chinese cohorts as gene discovery (n=2150) and three data sets of European ancestry populations for replication analysis of top association signals. Meta-analysis identified three single-nucleotide polymorphisms, rs936938 (P=4.49 10(-8)), non-synonymous rs6537835 (P=3.26 10(-8)) and rs1877455 (P=8.70 10(-8)), and related haplotypes, AMPD1-NRAS-CSDE1, TRIM33 and TRIM33-BCAS2, associated with autism; all were mapped to a previously reported linkage region (1p13.2) with autism. These genetic associations were further supported by a cis-acting regulatory effect on the gene expressions of CSDE1, NRAS and TRIM33 and by differential expression of CSDE1 and TRIM33 in the human prefrontal cortex of post-mortem brains between subjects with and those without autism. Our study suggests TRIM33 and NRAS-CSDE1 as candidate genes for autism, and may provide a novel insight into the etiology of autism.
Ellinghaus D.,University of Kiel |
Baurecht H.,University of Kiel |
Baurecht H.,TU Munich |
Esparza-Gordillo J.,Max Delbrück Center for Molecular Medicine |
And 60 more authors.
Nature Genetics | Year: 2013
Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis. © 2013 Nature America, Inc. All rights reserved.