Genome-wide Association Studies Findings Research Articles

Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study.

We evaluated the association of 56 candidate SNPs identified in two published genome-wide association studies (GWAS) of uterine leiomyoma (UL), or fibroids, with the risk and tumor size in the multi-ethnic uterine fibroid study (NIEHS-UFS). The selected SNPs were genotyped in 916 premenopausal women of African American (AA) and European American (EA) descents and their association with the outcomes was evaluated in race-stratified models and in meta-analysis of risk in NIEHS-UFS and discovery and replication GWAS in the Japanese population. We report moderate associations of variant rs4954368 in THSD7B (thrombospondin, type I, domain containing 7B) with tumor size in pooled analysis of AA and EA samples (P = 0.004), and at TNRC6B (trinucleotide repeat containing 6B) variants rs138039 and rs139909 in EA (P = 0.001 and 0.008, respectively). The most significant associations with risk in meta-analysis were observed at TNRC6B variants rs739182 (P = 3.7 × 10−10) and rs2072858 (P = 1.1 × 10−9) and were stronger than those reported in the discovery GWAS (P = 2.01 × 10−8 and 2.58 × 10−8, respectively). The present study failed to replicate the associations reported for CCDC57 and FASN in a discovery GWAS in populations of European descent. Consistent with previous replication studies in the Right From the Start Study (RFTS) and the BioVU DNA repository, we provide independent evidence for association of TNRC6B with both risk and size of UL. The present study is the first to report a replicated association of THSD7B with UL, albeit with tumor size and not with risk.

Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury.

Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The ‘response to microorganisms’ was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the ‘neuron projection morphogenesis’ process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection morphogenesis', which have been never anticipated in ALI pathogenesis, promotes lung-protective effects of LVT with high levels of PEEP.

Combined Whole Methylome and Genomewide Association Study Implicates CNTN4 in Alcohol Use.

Methylome-wide association (MWAS) studies present a new way to advance the search for biological correlates for alcohol use. A challenge with methylation studies of alcohol involves the causal direction of significant methylation-alcohol associations. One way to address this issue is to combine MWAS data with genomewide association study (GWAS) data. Here, we combined MWAS and GWAS results for alcohol use from 619 individuals. Our MWAS data were generated by next-generation sequencing of the methylated genomic DNA fraction, producing over 60million reads per subject to interrogate methylation levels at ~27million autosomal CpG sites in the human genome. Our GWAS included 5,571,786 single nucleotide polymorphisms (SNPs) imputed with 1000 Genomes. When combining the MWAS and GWAS data, our top finding was a region in an intron of CNTN4 (p=2.55×10(-8) ), located between chr3: 2,555,403 and 2,555,524, encompassing SNPs rs1382874 and rs1382875. This finding was then replicated in an independent sample of 730 individuals. We used bisulfite pyrosequencing to measure methylation and found significant association with regular alcohol use in the same direction as the MWAS (p=0.021). Rs1382874 and rs1382875 were genotyped and found to be associated in the same direction as the GWAS (p=0.008 and p=0.009). After integrating the MWAS and GWAS findings from the replication sample, we replicated our combined analysis finding (p=0.0017) in CNTN4. Through combining methylation and SNP data, we have identified CNTN4 as a risk factor for regular alcohol use.

MOBAS: identification of disease-associated protein subnetworks using modularity-based scoring.

Network-based analyses are commonly used as powerful tools to interpret the findings of genome-wide association studies (GWAS) in a functional context. In particular, identification of disease-associated functional modules, i.e., highly connected protein-protein interaction (PPI) subnetworks with high aggregate disease association, are shown to be promising in uncovering the functional relationships among genes and proteins associated with diseases. An important issue in this regard is the scoring of subnetworks by integrating two quantities: disease association of individual gene products and network connectivity among proteins. Current scoring schemes either disregard the level of connectivity and focus on the aggregate disease association of connected proteins or use a linear combination of these two quantities. However, such scoring schemes may produce arbitrarily large subnetworks which are often not statistically significant or require tuning of parameters that are used to weigh the contributions of network connectivity and disease association.Here, we propose a parameter-free scoring scheme that aims to score subnetworks by assessing the disease association of interactions between pairs of gene products. We also incorporate the statistical significance of network connectivity and disease association into the scoring function. We test the proposed scoring scheme on a GWAS dataset for two complex diseases type II diabetes (T2D) and psoriasis (PS). Our results suggest that subnetworks identified by commonly used methods may fail tests of statistical significance after correction for multiple hypothesis testing. In contrast, the proposed scoring scheme yields highly significant subnetworks, which contain biologically relevant proteins that cannot be identified by analysis of genome-wide association data alone. We also show that the proposed scoring scheme identifies subnetworks that are reproducible across different cohorts, and it can robustly recover relevant subnetworks at lower sampling rates.

Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic

The Psychiatric Genomics Consortium–Schizophrenia Workgroup (PGC–SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12–15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC–SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC–SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC–SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point.

Relative performance of gene- and pathway-level methods as secondary analyses for genome-wide association studies

BackgroundDespite the success of genome-wide association studies (GWAS), there still remains “missing heritability” for many traits. One contributing factor may be the result of examining one marker at a time as opposed to a group of markers that are biologically meaningful in aggregate. To address this problem, a variety of gene- and pathway-level methods have been developed to identify putative biologically relevant associations. A simulation was conducted to systematically assess the performance of these methods. Using genetic data from 4,500 individuals in the Wellcome Trust Case Control Consortium (WTCCC), case–control status was simulated based on an additive polygenic model. We evaluated gene-level methods based on their sensitivity, specificity, and proportion of false positives. Pathway-level methods were evaluated on the relationship between proportion of causal genes within the pathway and the strength of association.ResultsThe gene-level methods had low sensitivity (20-63%), high specificity (89-100%), and low proportion of false positives (0.1-6%). The gene-level program VEGAS using only the top 10% of associated single nucleotide polymorphisms (SNPs) within the gene had the highest sensitivity (28.6%) with less than 1% false positives. The performance of the pathway-level methods depended on their reliance upon asymptotic distributions or if significance was estimated in a competitive manner. The pathway-level programs GenGen, GSA-SNP and MAGENTA had the best performance while accounting for potential confounders.ConclusionsNovel genes and pathways can be identified using the gene and pathway-level methods. These methods may provide valuable insight into the “missing heritability” of traits and provide biological interpretations to GWAS findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0191-2) contains supplementary material, which is available to authorized users.

Strategies for elucidating functional significance of complex disease related loci

Genome-wide association studies (GWAS) have identified thousands of genetic loci associated with complex diseases or traits. However, the exact biological functions of these loci are largely unknown. Recent functional annotation indicates that the majority of disease/trait associated loci are concentrated in regulatory DNA of human genome. Expression quantitative trait loci (eQTL) analyses, chromosome conformation capture related methods and genome editing methods (such as CRISPR/Cas9) may facilitate the functional study of these loci. Research on noncoding RNAs and rare variants may improve the functional understanding. These efforts may promise translation of GWAS findings to clinical practices.

Patterns of linkage disequilibrium at PARK16 may explain variances in genetic association studies.

Reproducing genomewide association studies findings in different populations is challenging, because the reproducibility fundamentally relies on the similar patterns of linkage disequilibrium between the unknown causal variants and the genotyped single-nucleotide polymorphisms (SNPs). The PARK16 locus was reported to alter the risk of Parkinson's disease (PD) in genomewide association studies in Japanese and Caucasians. We evaluated the regional linkage disequilibrium pattern at PARK16 locus in Caucasians, Japanese, and Chinese from HapMap and Chinese, Malays, and Indians from the Singapore Genome Variation Project, using the traditional heatmaps and targeted analysis of PARK16 gene via Monte Carlo simulation through varLD scores of these ethnic groups. One hundred SNPs in Caucasians, 95 SNPs in Chinese, 78 SNPs in Japanese from HapMap, 86 SNPs in Chinese, 99 SNPs in Indians, and 97 SNPs in Malays from the Singapore Genome Variation Project were included. Our targeted analysis showed that the linkage disequilibrium pattern of SNPs close to rs947211 was similar in Caucasians and Asians, including Chinese, Japanese, and Malay (all P > 0.0001), whereas different linkage disequilibrium patterns around rs823128, rs823156, and rs708730 were found between Caucasians and these Asian groups (all P < 0.0001). Our study suggests a higher chance to detect the association between rs947211 and PD in Chinese, Malay, and other Caucasian groups because of the similar linkage disequilibrium pattern around rs947211. The associations between rs823128/rs823156/rs708730 and PD are more likely to be replicated in Chinese and Malay populations.

Genome-Wide Association Study of Short-Acting β2-Agonists. A Novel Genome-Wide Significant Locus on Chromosome 2 near ASB3

β2-Agonists are the most common form of treatment of asthma, but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable. To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. The combined P value for four SNPs reached statistical genome-wide significance aftercorrecting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 × 10(-10), 5.75 × 10(-8), 9.3 × 10(-8), and 3.95 × 10(-8), respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population. These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.

Genetic determinants of chronic oxaliplatin-induced peripheral neurotoxicity: a genome-wide study replication and meta-analysis.

We aimed at validating the role of genetic variants identified by a recent genome-wide association study (GWAS) as determinants of chronic oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin-based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI-CTC criteria and the clinical version of the Total Neuropathy Score(©) (TNSc(©) ). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI-CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc(©) scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10-0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI-CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI-CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40-5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P-value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta-analysis for validation of GWAS findings.

The genome as pharmacopeia: Association of genetic dose with phenotypic response

The majority of compounds that enter clinical trials fail to meet regulatory standards for marketed therapeutics. Success in clinical trials is increased when therapies are directed against targets for which genetic variants have been linked to disease risk or progression in humans. Here we review how genome-wide association studies (GWAS) have furthered our understanding of the genetic basis of common disease, and how GWAS findings could stimulate development of novel drugs. Genetic screens that associate variants with clinical phenotypes of interest, like pharmacological screens that associate compounds with in vitro responses of interest, establish an intervention–response relationship on which a therapeutic hypothesis can be based. We highlight the similarities between the GWAS approach and well-established principles in early drug discovery, from primary screen through lead identification. We believe that integration of genetic and pharmacological screens will considerably enhance the development of therapeutic interventions with clear benefit to patients.

A systems genetics study of swine illustrates mechanisms underlying human phenotypic traits.

BackgroundThe pig, which shares greater similarities with human than with mouse, is important for agriculture and for studying human diseases. However, similarities in the genetic architecture and molecular regulations underlying phenotypic variations in humans and swine have not been systematically assessed.ResultsWe systematically surveyed ~500 F2 pigs genetically and phenotypically. By comparing candidates for anemia traits identified in swine genome-wide SNP association and human genome-wide association studies (GWAS), we showed that both sets of candidates are related to the biological process “cellular lipid metabolism” in liver. Human height is a complex heritable trait; by integrating genome-wide SNP data and human adipose Bayesian causal network, which closely represents bone transcriptional regulations, we identified PLAG1 as a causal gene for limb bone length. This finding is consistent with GWAS findings for human height and supports the common genetic architecture between swine and humans. By leveraging a human protein-protein interaction network, we identified two putative candidate causal genes TGFB3 and DAB2IP and the known regulators MESP1 and MESP2 as responsible for the variation in rib number and identified the potential underlying molecular mechanisms. In mice, knockout of Tgfb3 and Tgfb2 together decreases rib number.ConclusionOur findings show that integrative network analyses reveal causal regulators underlying the genetic association of complex traits in swine and that these causal regulators have similar effects in humans. Thus, swine are a potentially good animal model for studying some complex human traits that are not under intense selection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1240-y) contains supplementary material, which is available to authorized users.

Optimizing multiple sclerosis diagnosis: gene expression and genomic association.

ObjectiveThe diagnosis of multiple sclerosis (MS) at disease onset is sometimes masqueraded by other diagnostic options resembling MS clinically or radiologically (NonMS). In the present study we utilized findings of large-scale Genome-Wide Association Studies (GWAS) to develop a blood gene expression-based classification tool to assist in diagnosis during the first demyelinating event.MethodsWe have merged knowledge of 110 MS susceptibility genes gained from MS GWAS studies together with our experimental results of differential blood gene expression profiling between 80 MS and 31 NonMS patients. Multiple classification algorithms were applied to this cohort to construct a diagnostic classifier that correctly distinguished between MS and NonMS patients. Accuracy of the classifier was tested on an additional independent group of 146 patients including 121 MS and 25 NonMS patients.ResultsWe have constructed a 42 gene-transcript expression-based MS diagnostic classifier. The overall accuracy of the classifier, as tested on an independent patient population consisting of diagnostically challenging cases including NonMS patients with positive MRI findings, achieved a correct classification rate of 76.0 ± 3.5%.InterpretationThe presented diagnostic classification tool complements the existing diagnostic McDonald criteria by assisting in the accurate exclusion of other neurological diseases at presentation of the first demyelinating event suggestive of MS.

Exploring hypertension genome-wide association studies findings and impact on pathophysiology, pathways, and pharmacogenetics.

Hypertension is a major risk factor for global mortality. Recent genome-wide association studies (GWAS) have led to successful identification of many genetic loci influencing blood pressure, although these studies account for less than 5% of heritability. While genetic discovery efforts continue, it is timely to pause and reflect on what information has been gained to date from reported loci. Knowledge from GWAS findings inform our understanding of the pathways and pleiotropy underpinning hypertension and aid in the identification of potential druggable targets. By reviewing blood pressure loci we aim to determine how much potential the current observations have for future clinical utility. The authors have declared no conflicts of interest for this article.

Gene Expression in Transformed Lymphocytes Reveals Variation in Endomembrane and HLA Pathways Modifying Cystic Fibrosis Pulmonary Phenotypes

Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P.aeruginosa)lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. LPAR6, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent P. aeruginosa infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease.

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

AbstractAcute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10−8 in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10−10) and rs3781093, OR, 1.73 (P = 3.2 × 10−9). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non–Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10−11). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

A common FUT2 variant correlates with serum carcinoembryonic antigen levels and affects cancer screening in patients with primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) can be complicated by the development of biliary malignancy as cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCA). Besides the most commonly used serum screening parameter, namely CA19 – 9, screening with serum levels of carcinoembryonic antigen (CEA) is less examined. We thus conducted a study to investigate carcinoembryonic antigen (CEA) as a screening parameter for biliary malignancy in PSC patients. Based upon findings of a recent genome-wide association study that described an association between the genes of fucosyltransferases (FUT) and CEA, we thought to analyze how serum CEA levels were affected by common genetic variants of FUT2 and FUT3.

Path from schizophrenia genomics to biology: gene regulation and perturbation in neurons derived from induced pluripotent stem cells and genome editing.

Schizophrenia (SZ) is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies (GWASs) of SZ have identified >100 risk loci. However, the causal variants/genes and the causal mechanisms remain largely unknown, which hinders the translation of GWAS findings into disease biology and drug targets. Most risk variants are noncoding, thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling, and open chromatin is a versatile predictor of regulatory sequences. MicroRNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs) provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specific to cell type and/or developmental stage. The emerging genome-editing technology enables the creation of isogenic iPSCs and neurons to efficiently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic, glutamatergic, and GABAergic neurotransmissions. SZ GWAS findings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.

GWAS and Meta-Analysis in Aging/Longevity.

Longevity is an extremely complex phenotype that is determined by environment, life style and genetics. Genome wide association studies (GWAS) have been a powerful tool to identify the genetic origin of other complex outcome with a similar heritability. In this chapter we discuss the findings all GWAS of longevity conducted to date. Various cut-off to define longevity have been used varying from 85+, 90+ and 100+ years and the impact of these difference are addressed in this chapter. The only consistent association emerging from GWAS to data is the APOE gene that has been already identified as a candidate gene. Although (GWAS) have identified biologically plausible genes and pathways, no new loci for longevity have been conclusively proven. A reason for not finding any replicated associations for longevity could be the complexity of the phenotype, although heterogeneity also underlies many other traits for which GWAS has been successful. One may argue that rare variants explain the high heritability of longevity and the segregation of the trait in families. Yet, whole genome analyses of GWAS data still suggest that over 80 % of the heritability is explained by common variants. Although findings of GWAS to date have been disappointing, there is ample opportunity to improve the statistical power of studies to find common variants with small effects. In the near future, joining of the published studies and new ones emerging may bring to surface new loci.

Correlation between natriuretic peptide receptor C (NPR3) gene polymorphisms and hypertension in the Dai people of China.

Hypertension affects one-fifth of the world population. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) that correlated with hyper-tension in large samples. However, the genetic mutations leading to hypertension might differ among various populations, as they have different origins and are subjected to different environmental pressures. Therefore, additional studies are urgently needed to verify the GWAS findings across different populations. This study focused on the natriuretic peptide receptor C gene (NPR3), one of the hypertension-positive genes identified in a GWAS of an East Asian population. The correlation analysis between NPR3 and hypertension was replicated in 450 Chinese Dai (235 patients vs 215 controls) and 484 Chinese Mongolian (211 patients vs 273 controls) individuals. The positive SNP identified by GWAS analysis and three other tag SNPs representing the NPR3 linkage disequilibrium (LD) block regions were selected for genotyping. The results revealed that the rs1173766 polymorphism was associated with the occurrence of hypertension (χ(2) = 6.87, P = 0.0088), and that the T allele should be protective in the Dai ethnic group. Consider-ing a close LD block at the 3' end of the NPR3 gene in the East Asian population, we speculate that there might be a mutation in the last five exons or the 3' untranslated region of NPR3 that could change the structure or expression of the NPR3 gene. However, in the Mongolian ethnic group, these SNPs were not associated with the incidence of hypertension, suggesting population heterogeneity for the genetic factors that contribute to hypertension.