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Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer., Chinese breast cancer patients have not been well represented in clinical sequencing studies. Here the authors analyse the mutational landscape of 1,134 Chinese breast cancer patients, finding actionable targets and a higher prevalence of p53 and Hippo pathway mutations compared to Western cohorts.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Background: Genetics and lifestyle behaviors are key contributors to obesity. However, few studies explicitly examine the differential genetic association with BMI across critical lifecycle periods between young adulthood and later adulthood. Hypothesis: We anticipate that genetic risk will be directly associated with BMI in young adulthood and there will be a strong indirect association with BMI later in life, as a result the increased risk of BMI associated with young adulthood. Methods: For 7,397 Chinese adult participants (age 18 to 65y) of the China Health and Nutrition Survey (CHNS; 1991-2015), we calculated an obesity polygenic risk score (PRS) based on BMI-related SNPs selected from the largest BMI GWAS in 700,000 individuals of European ancestry from UK biobank and GIANT consortium, weighted by effect size estimated from the GWAS study. We used linear mixed models to estimate BMI across all periods of adulthood, adjusting for calendar time and sex. In a subsample of participants with three measurements across 24 years (n=1220), we used pathway based analysis to estimate the direct effects of genetic risk in association with BMI during young (18-35y), middle (35-45y), and later (45-65y) adulthood as well as the indirect genetic effects of at later adulthood through BMI at each of these earlier periods in life. Results: In the full sample, the linear mixed model-adjusted mean BMI (Standard Error (SE)) was 22.4 (0.04) kg/m 2 at young adulthood, 23.1 (0.04) kg/m 2 at middle adulthood and 23.2 (0.04) kg/m 2 at later adulthood, adjusting for sex and calendar year. In the subsample, a one standard deviation higher obesity PRS was directly associated with a 0.38 (0.07 SE) and 0.21 (0.06 SE) kg/m 2 higher BMI in young and middle adulthood, respectively. We found no evidence of a direct estimated effect of PRS in later adulthood (age 45-64y), but evidence of an indirect association between obesity PRS and BMI in later adulthood (age 45-64y). For example, we found a one standard deviation higher PRS was indirectly associated with 0.31 (0.06 SE) kg/m 2 higher BMI at age 35-45y through BMI at age 18-35y, and a 0.25 (0.05 SE) kg/m 2 higher BMI at age 45-65y through BMI at age 18-35y and subsequently BMI at age 35-45y. Conclusion: We observed a strong direct association between polygenic risk for obesity in young adulthood (age 18-35y), with persistence through age 35-45y and into age 45-65y.

To characterize the prevalence of BRCA mutations and characteristics of BRCA carriers in China and to update the clinical recommendations for BRCA testing, we conducted a wide screen for BRCA mutations using next-generation sequencing (NGS). A total of 4,034 Chinese subjects were screened for germline BRCA1/2 mutations, including 2,991 breast cancer patients and 1,043 healthy individuals from the community enrolled as controls. We developed an NGS-based approach to perform BRCA1/2 screening. BRCA mutations were identified in 9.1% (232/2,560) of cases with at least one risk factor, in 3.5% (15/431) of sporadic patients and in 0.38% (4/1,043) of healthy controls. The mutation frequency ranged from 8.9 to 15.2% in cohorts with a single risk factor to 16.6–100% in groups with multiple risk factors. We identified 70 novel BRCA mutations. A high frequency of BRCA1 c.5470_5477del was detected, accounting for 13.9% (16/115) of the BRCA1 mutations detected in our study. Clinical characteristics such as family history, invasive carcinoma, negative human epidermal growth factor receptor 2 (HER2), high Ki67 index, lymph node status, and high tumour grade were closely related to BRCA mutations. BRCA2 carriers had poorer disease-free survival among HER2- or hormone receptor-positive patients (hazard ratio = 1.892; 95% confidence interval: 1.132–3.161; p = 0.013). This study shows that BRCA mutation carriers could be frequently identified among breast cancer patients with multiple risk factors. Importantly, we established an NGS-based pipeline for BRCA1/2 testing in clinical practice and strongly suggest that breast cancer patients of premier- and moderate-grade risks receive BRCA1/2 mutations testing in China.

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P

Purpose: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. Experimental Design: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. Results: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the “immune-desert” cluster, with low microenvironment cell infiltration; cluster 2, the “innate immune-inactivated” cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the “immune-inflamed” cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathologic sections and externally with The Cancer Genome Atlas and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. Conclusions: Our study represents a step toward personalized immunotherapy for patients with TNBC. Immune checkpoint inhibitors might be effective for “immune-inflamed” cluster, and the transformation of “cold tumors” into “hot tumors” should be considered for “immune-desert” and “innate immune-inactivated” clusters.

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

Background Hypospadias is a common congenital malformation of male external genitalia, which mainly manifests as an abnormal urethral opening on the ventral side of the penis. The etiology and clinical phenotype of hypospadias is highly heterogeneous, and its clinical diagnosis is challenging. Currently, over 70% of patients have an unknown etiology. Here, we performed a targeted analysis of gene mutations in 130 patients with hypospadias of unknown etiology to find the precise genetic cause. Methods We developed a targeted next‐generation sequencing (NGS) panel, encompassing the exon coding regions of 105 genes involved in external genitalia and urogenital tract development and performed sequencing analysis on 130 children with hypospadias of unknown etiology. Results In total, 25 patients with hypospadias (19.2%) were found to have 20 mutations among the nine genes involved in external genitalia and urogenital tract development, including 16 reported and four novel mutation sites. Twenty‐two patients (16.9%) had diagnostic variants. Multiple genetic mutations were identified in three of the 25 patients. Hypospadias combined with micropenis was the most common phenotype (68%) in 25 patients. Conclusions Higher frequency mutations were identified in SRD5A2 (52%) and AR (24%) in our patient cohort. Middle or posterior hypospadias with micropenis may be significant indicators of genetic variations. Polygenic inheritance may be a rare genetic cause of hypospadias.

Background Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening. Methods Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed. Results The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia. Conclusions Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management.

Background We conducted this study to investigate the prevalence of potential chemo-response-related gene mutations in triple-negative breast cancer (TNBC) patients and to evaluate the potential relationship between these gene mutations and neoadjuvant chemotherapy response in TNBC patients. Methods One hundred sixty-two TNBC patients in Fudan University Shanghai Cancer Center who received NAC with 4 cycles of paclitaxel and carboplatin were enrolled in this study. Fifty-six pathological complete response (pCR) patients and 56 non-pCR patients were enrolled in this retrospective study for the training set. Clinical assessments of postoperative residual tumors were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Forty chemo-response-related genes were screened in each tumor specimen by second-generation sequencing analysis. Fifty TNBC patients who received neoadjuvant chemotherapy with paclitaxel and carboplatin were enrolled in the validation group. Results Fifty-seven of 112 (50.9%) TNBCs contained at least one detected somatic mutation. As expected, TP53 mutation was the most common alteration, which was observed in 21.4% of patients. BRCA1, BRCA2, RET, PI3KCA, and PTEN mutations were each observed in 11.6%, 4.5%, 5.4%, 2.7% and 3.6% of all cases, respectively. No significant differences in any gene mutation frequency between pCR and non-pCR groups were identified. We found that the mutation status of 10 DNA repair genes involved in homologous recombination (HR) pathway successfully discriminated between responding and nonresponding tumors in the training group. Up to 18 patients who were mutation-positive experienced pCR compared to only 6 in the non-pCR group (P=0.006), and 75% the HR related gene mutation patients achieved pCR. In the validation group, TNBC patients with DNA repair gene mutations achieved 77.8% pCR. Conclusions A subset of TNBC patients carry deleterious somatic mutations in 10 HR-related genes. The mutation status of this expanded gene panel is likely to effectively predict respond rate to neoadjuvant chemotherapy based on paclitaxel and carboplatin. Our findings need to be validated through follow-up studies in this and additional cohorts.

Background Hereditary factors contributed to breast cancer susceptibility. Low BRCA mutation prevalence was demonstrated in previous BRCA mutation screening in Chinese breast cancer patients. Multiple-gene sequencing may assist in discovering detrimental germline mutation in. Brca negative breast cancers. Methods A total of 384 Chinese subjects with any two of high-risk factors were recruited and screened by next-generation sequencing (NGS) for 30 cancer susceptible genes. Variants with a truncating, initiation codon or splice donor/acceptor effect, or with pathogenicity demonstrated in published literature were classified into pathogenic/likely-pathogenic mutations. Results In total, we acquired 39 (10.2%) patients with pathogenic/likely-pathogenic germline mutations, including one carrying two distinct mutations. Major mutant non-BRCA genes were MUTYH (n=11, 2.9%), PTCH1 (n=7, 1.8%), RET (n=6, 1.6%) and PALB2 (n=5, 1.3%). Other mutant genes included TP53 (n=3, 0.8%), RAD51D (n=2, 0.5%), CHEK2 (n=1, 0.3%), BRIP1 (n=1, 0.3%), CDH1 (n=1, 0.3%), MRE11 (n=1, 0.3%), RAD50 (n=1, 0.3%) and PALLD (n=1, 0.3%). A splicing germline mutation, MUTYH c.934-2A>G, was a hotspot (9/384, 2.3%) in Chinese breast cancer. Conclusions Among BRCA-negative breast cancer patients with high hereditary risk in China, 10.2% carried mutations in cancer associated susceptibility genes. MUTYH and PTCH1 had relatively high mutation rates (2.9% and 1.8%). Multigene testing contributes to understand genetic background of BRCA-negative breast cancer patients with high hereditary risk.

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.

Hypertension is an important risk factor for cardiovascular disease, the leading cause of mortality all over the globe.1 Hypertension is a worldwide problem2 and its prevalence is increasing in China.3 According to the data from the 2007–2008 China National Diabetes and Metabolic Disorders Study, 26.6% of Chinese adults have hypertension,3 causing considerable health and economic burden.4,5 The etiology of high blood pressure involves the interplay among many factors. Risk factors include body mass index (BMI), tobacco use, salt and alcohol intake, and physical activity.6 An estimated 30–60% of blood pressure variation is explained by genetic factors.7 Many genetic variants have been identified by genome-wide association studies conducted in multiple populations. Blood pressure is a complex phenotype, and the effects of some variants may be stronger in individuals exposed to specific environmental factors. However, relatively few studies have investigated the possible interaction between genetic variants and environmental factors in affecting blood pressure. Several loci first identified in subjects of European descent, including ATP2B1 on chromosome 12q21.33, FGF5 on 4q21.21, CYP17A1 on 10q24.32, and CSK on 15q24.1 have been validated in East Asians.8,9 In this study, we genotyped index variants from these 4 candidate loci and examined whether the associations with systolic (SBP) and diastolic (DBP) blood pressure could be replicated in 7,319 adults (18 years and older) from 9 provinces in the China Health and Nutrition Survey (CHNS). We further tested whether the associations were influenced by environmental factors including age, sex, and BMI. Finally, we attempted to replicate specific findings in 1,996 men from the Fangchenggang Area Male Health and Examination Survey (FAMHES).

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to 7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2, we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3, SIX2, and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2, we tested five candidate variants for allelic differences in regulatory function. The rs12712928-C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus., Author summary Type 2 diabetes risk and levels of glucose, insulin, and HbA1c are heritable traits correlated with risk of other diseases and mortality. To identify genetic variants associated with these traits, we studied up to 7,178 men and women from nine provinces in China. We found established variants that could affect fasting glucose located in or near genes named G6PC2 and SIX3. One of the variants at G6PC2 changes the protein sequence and is predicted to affect how the protein functions. Variants located near SIX3 that are associated with levels of glucose are also associated with levels of expression of the genes SIX3 and SIX2 in pancreatic islets. These variants are located in a genomic region predicted to enhance gene expression. We used laboratory assays to show that alleles at one variant, rs12712928, demonstrate significant differences in transcriptional activity, suggesting that this variant influences levels of the SIX3 and SIX2 genes in islets, ultimately increasing glucose levels.

Apolipoprotein A5 (APOA5) gene plays a key role in plasma triglyceride (TG) metabolism, and shows the involvement in coronary artery disease (CAD). A set of single nucleotide polymorphisms around the APOA5 gene was identified to be associated with plasma TG levels. It is of biological and clinical importance to discern the genuine genetic determinants. A polymorphism in 3′ untranslated region of the APOA5 gene, rs2266788, is deserving of investigation for suggestive clues from the association in multiple independent studies. In this study, rs2266788 was genotyped in 3222 unrelated subjects consisting of 2062 CAD cases and 1160 controls. The statistical analyses indicated that the minor C allele of rs2266788 was significantly associated with elevated plasma TG levels and higher CAD risk. In normal human liver tissues, comparison of global APOA5 mRNA levels among genotypes and allelic expression imbalance analysis showed the decreased gene expression for the C allele. Luciferase assays confirmed a concordant result that transcriptional activity was lowered for the C allele compared with the T allele in four cell lines. Multiple lines of evidence in our study supported that rs2266788 was causally associated with plasma TG levels conferring CAD risk in Han Chinese population owing to a cis-acting effect to the APOA5 gene expression.

Background Graves’ disease is a female preponderant autoimmune illness and the contribution of the X chromosome to its risk has long been appreciated. However, no X-linked susceptibility loci have been indentified from recent genome-wide association studies (GWAS). Methods We re-examined the X chromosome data from our recent GWAS for Graves’ disease by including males that were previously excluded from the X chromosome analyses. The data were analysed using logistic regression analysis including sex as a covariate, and an additive method assuming X chromosome inactivation, implemented in snpMatrix. Results A cluster of single nucleotide polymorphism (SNPs) at Xq21.1 was found showing association with genome-wide significance, among which rs3827440 was a non-synonymous SNP of GPR174 (Plogistic regression= 9.52×10−8; PsnpMatrix=4.60×10−9; OR=1.76, 95% CI 1.45 to 2.13). The association was reproduced in an independent sample collection set including 4564 Graves’ disease cases and 3968 sex matched controls (combined Plogistic regression=5.53×10−21; combined PsnpMatrix=4.26×10−22; OR=1.69, 95% CI 1.53 to 1.86). Notably, GPR174 was widely expressed in immune related tissues and rs3827440 genotypes were associated with distinct mRNA levels (p=0.002). GPR174 did not show sex biased gene expression in our expression analysis. Resequencing study suggested the contribution of some rare variants in the GPR174 gene region to disease risk with a collapsing p value of 1.16×10−3. Conclusions The finding of an X-linked risk locus for Graves’ disease expands our understanding of the role of the X chromosome in disease susceptibility.

Background 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. Methodology/Principal Findings We performed a case-control association study with 2,335 coronary atherosclerosis patients and 1,078 controls undergoing coronary angiography of Chinese Han from China. Fourteen single nucleotide polymorphisms (SNPs), located at 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21 and 15q22.33, were genotyped in our sample collection. Six SNPs at 9p21 were associated with coronary atherosclerosis susceptibility (Ptrend

Variations in the activities of Cytochrome P450s are one of the major factors responsible for inter-individual differences in drug clearance rates, which may cause serious toxicity or inefficacy of therapeutic drugs. Various mRNA level is one of the key factors for different activity of the major P450 genes. Although both genetic and environmental regulators of P450 gene expression have been widely investigated, few studies have evaluated the functional importance of cis- and trans-regulatory factors and environmental factors in the modulation of inter-individual expression variations of the P450 genes. In this study, we measured the mRNA levels of seven major P450 genes (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5) in 96 liver biopsy samples from Chinese population. Both trans-acting (mRNA levels and non-synonymous SNPs of putative regulator genes) and cis-acting (gene copy number and functional SNPs) factors were investigated to identify the determinants of the expression variations of these seven P450 genes. We found that expression variations of most P450 genes, regulator genes and housekeeping genes were positively correlated at the mRNA level. After partial correlation analysis using ACTB and GAPDH expression to eliminate the effect of global regulators, a UPGMA (Unweighted Pair Group Method with Arithmetic Mean) tree was constructed to reveal the effects of specific regulation networks potentially masked by global regulators. Combined with the functional analysis of regulators, our results suggested that expression variation at the mRNA level was mediated by several factors in a gene-specific manner. Cis-acting genetic variants might play key roles in the expression variation of CYP2D6 and CYP3A5, environmental inducers might play key roles in CYP1A1 and CYP1A2 variation and global regulators might play key roles in CYP2C9 variation. In addition, the functions of regulators that play less important roles in controlling expression variation for each P450 gene were determined.

With the completion of Human Genome Project, International HapMap Project and the publication of copy number variation in human genome, a great number of accurate, rapid, and cost-effective technologies for SNP analysis have been developed, promoting the research of the complex diseases. This article presents a review of widely used genotyping techniques, and the progress and prospect in the study of complex diseases in terms of the projects and achievements of Chinese National Human Genome Center at Shanghai (CHGCs).

Catalase is an important antioxidant enzyme that detoxifies H2O2 into oxygen and water and thus limits the deleterious effects of reactive oxygen species (ROS). Because chronic exposure to excess ROS may contribute to vascular damage, we investigated whether genetic variation in catalase was associated with susceptibility to essential hypertension (EHYT) in 324 individuals (at least 50 years old) who were randomly sampled from an isolated population living in Xiangchang, China. They were screened for genetic variation in the promoter of catalase by direct sequencing. In total, four single nucleotide polymorphisms (SNPs) were identified. The association between the SNPs and EHYT was investigated by a linear regression model under phenotypic selection; in our analyses, we used both SBP>150 mmHg and SBP>160 mmHg as thresholds. A SNP 844 bp upstream of the start codon (SNP-844) demonstrated strong evidence of association with EHYT (SBP>150 mmHg: F=5.09, P=0.008; SBP>160 mmHg: F=7.13, P=0.002). This is the first study to implicate genetic variation in catalase in susceptibility to EHYT and suggests that polymorphisms in promoter regions may be particularly relevant to the study of complex diseases.

In order to comprehensively screen genetic variants leading to differential expression of the important human ABCB1 gene in the primary drug-metabolizing organ, ABCB1 mRNA expression levels were measured in 73 normal liver tissue samples from Chinese subjects. A set of Tag SNPs. were genotyped. In addition, imputation was performed within a 500 kb region around the ABCB1 gene using the reference panels of 1,000 Genome project and HapMap III. Bayesian regression was used to assess the strength of associations by compute Bayes Factors for imputed SNPs. Through imputation and linkage disequilibrium analysis, the imputed loci rs28373093, rs1002205, rs1029421, rs2285647, and rs10235835, may represent independent and strong association signals. rs28373093, a polymorphism 1.5 kb upstream from the ABCB1 transcription start site, has the strongest association. 2677 G>A/T and 3435C>T confer a clear gene-dosage effect on ABCB1 mRNA expression. The systematic characterization of gene-wide common quantitative trait loci associated with ABCB1 mRNA expression in normal liver tissues would provide the candidate markers to ABCB1-relevant clinical phenotypes in Chinese population.