在过去的5年中,全基因组关联研究(Genome-wide association study,GWAS)方法已被证明是研究复杂疾病和性状遗传易感变异的一种有效手段。目前,各国科学家在多种复杂疾病和性状中开展了大量的GWAS,对肿瘤、糖尿病、心脏病、神经精神疾病...在过去的5年中,全基因组关联研究(Genome-wide association study,GWAS)方法已被证明是研究复杂疾病和性状遗传易感变异的一种有效手段。目前,各国科学家在多种复杂疾病和性状中开展了大量的GWAS,对肿瘤、糖尿病、心脏病、神经精神疾病、自身免疫及免疫相关疾病等复杂疾病以及一些常见性状(如身高、体重、血脂、色素等)的遗传易感基因研究取得了重大成果。截止到2010年9月11日,运用GWAS开展了对近200种复杂疾病/性状的研究,发现了3000多个疾病相关的遗传变异。文章就GWAS的发展及其在复杂疾病/性状中的应用做一综述。展开更多
Type 2 diabetes mellitus(T2DM) is a complex disease in which both genetic and environmental factors interact in determining impaired β-cell insulin secretion and peripheral insulin resistance. Insulin resistance in m...Type 2 diabetes mellitus(T2DM) is a complex disease in which both genetic and environmental factors interact in determining impaired β-cell insulin secretion and peripheral insulin resistance. Insulin resistance in muscle, liver and fat is a prominent feature of most patients with T2DM and obesity, resulting in a reduced response of these tissues to insulin. Considerable evidence has been accumulated to indicate that heredity is a major determinant of insulin resistance and T2DM. It is believed that, among individuals destined to develop T2DM, hyperinsulinemia is the mechanism by which the pancreatic β-cell initially compensates for deteriorating peripheral insulin sensitivity, thus ensuring normal glucose tolerance. Most of these people will develop T2DM when β-cells fail to compensate. Despite the progress achieved in this field in recent years, the genetic causes of insulin resistance and T2DM remain elusive.Candidate gene association, linkage and genome-wide association studies have highlighted the role of genetic factors in the development of T2DM. Using these strategies, a large number of variants have been identified in many of these genes, most of which may influence both hepatic and peripheral insulin resistance, adipogenesis and β-cell mass and function. Recently, a new gene has been identified by our research group, the HMGA1 gene, whose loss of function can greatly raise the risk of developing T2DM in humans and mice. Functional genetic variants of the HMGA1 gene have been associated with insulin resistance syndromes among white Europeans, Chinese individuals and Americans of Hispanic ancestry. These findings may represent new ways to improve or even prevent T2DM.展开更多
Improved soybean cultivars have been adapted to grow at a wide range of latitudes,enabling expansion of cultivation worldwide.However,the genetic basis of this broad adaptation is still not clear.Here,we report the id...Improved soybean cultivars have been adapted to grow at a wide range of latitudes,enabling expansion of cultivation worldwide.However,the genetic basis of this broad adaptation is still not clear.Here,we report the identification of GmPRR3b as a major flowering time regulatory gene that has been selected during domestication and genetic improvement for geographic expansion.Through a genome-wide association study of a diverse soybean landrace panel consisting of 279 accessions,we identified 16 candidate quantitative loci associated with flowering time and maturity time.The strongest signal resides in the known flowering gene E2,verifying the effectiveness of our approach.We detected strong signals associated with both flowering and maturity time in a genomic region containing GmPRR3b.Haplotype analysis revealed that GmPRR3bH6 is the major form of GmPRR3b that has been utilized during recent breeding of modern cultivars.mRNA profiling analysis showed that GmPRR3bH6 displays rhythmic and photoperiod-dependent expression and is preferentially induced under long-day conditions.Overexpression of GmPRR3bH6 increased main stem node number and yield,while knockout of GmPRR3bH6 using CRISPR/Cas9 technology delayed growth and the floral transition.GmPRR3bH6 appears to act as a transcriptional repressor of multiple predicted circadian clock genes,including GmCCAIa,which directly upregulates J/GmELF3a to modulate flowering time.The causal SNP(Chr12:5520945)likely endows GmPRR3bH6 a moderate but appropriate level of activity,leading to early flowering and vigorous growth traits preferentially selected during broad adaptation of landraces and improvement of cultivars.展开更多
Genotyping and phenotyping large natural populations provide opportunities for population genomic analysis and genome-wide association studies(GWAS). Several rice populations have been re-sequenced in the past decade;...Genotyping and phenotyping large natural populations provide opportunities for population genomic analysis and genome-wide association studies(GWAS). Several rice populations have been re-sequenced in the past decade;however, many major Chinese rice cultivars were not included in these studies. Here, we report large-scale genomic and phenotypic datasets for a collection mainly comprised of 1,275 rice accessions of widely planted cultivars and parental hybrid rice lines from China. The population was divided into three indica/Xian and three japonica/Geng phylogenetic subgroups that correlate strongly with their geographic or breeding origins. We acquired a total of 146 phenotypic datasets for 29 agronomic traits under multi-environments for different subpopulations. With GWAS, we identified a total of 143 significant association loci, including three newly identified candidate genes or alleles that control heading date or amylose content. Our genotypic analysis of agronomically important genes in the population revealed that many favorable alleles are underused in elite accessions, suggesting they may be used to provide improvements in future breeding efforts. Our study provides useful resources for rice genetics research and breeding.展开更多
The clinical outcome of hepatitis B virus(HBV) infection depends on the success or failure of the immune responses to HBV,and varies widely among individuals,ranging from asymptomatic self-limited infection,inactive c...The clinical outcome of hepatitis B virus(HBV) infection depends on the success or failure of the immune responses to HBV,and varies widely among individuals,ranging from asymptomatic self-limited infection,inactive carrier state,chronic hepatitis,cirrhosis,hepatocellular carcinoma,to liver failure,depending on the success or failure of immune response to HBV.Genome-wide association studies(GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits.In this review,we discuss GWAS for persistence of HBV infection,antibody response to hepatitis B vaccine,and HBV-related advanced liver diseases.HBV persistence is associated with multiple genes with diverse roles in immune mechanisms.The strongest associations are found within the classical human leukocyte antigen(HLA) genes,highlighting the central role of antigen presentation in the immune response to HBV.Associated variants affect both epitope binding specificities and expression levels of HLA molecules.Several other susceptibility genes regulate the magnitude of adaptive immune responses,determining immunity vs tolerance.HBV persistence and nonresponse to vaccine share the same risk variants,implying overlapping genetic bases.On the other hand,the risk variants for HBV-related advanced liver diseases are largely different,suggesting different host-virus dynamics in acute vs chronic HBV infections.The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.展开更多
Excess salinity is a natural stress that causes crop yield losses worldwide. The genetic bases of maize salt tolerance remain largely unknown. Here we investigated the survival rates of 445 maize natural accessions af...Excess salinity is a natural stress that causes crop yield losses worldwide. The genetic bases of maize salt tolerance remain largely unknown. Here we investigated the survival rates of 445 maize natural accessions after salt treatments. A skewed distribution of the salttolerant phenotypes was observed in this population.Genome-wide association studies(GWAS) revealed 57 loci significantly associated with salt tolerance. Forty-nine candidate genes were detected from these loci. About10% of these genes were co-localized with loci from QTL mapping. Forty four percent of the candidate genes were involved in stress responses, ABA signaling,stomata division, DNA binding/transcription regulation and auxin signaling, suggesting that they are key genetic mechanisms of maize salt tolerance. Transgenic studies showed that two genes, the salt-tolerance-associatedgene 4(SAG4, GRMZM2 G077295) and SAG6(GRMZM2 G106056), which encode a protein transport protein and the double-strand break repair protein MRE11,respectively, had positive roles in plant salt tolerance,and their salt-tolerant haplotypes were revealed. The genes we identified in this study provide a list of candidate targets for further study of maize salt tolerance, and of genetic markers and materials that may be used for breeding salt-tolerance in maize.展开更多
Although genome-wide association studies are widely used to mine genes for quantitative traits,the effects to be estimated are confounded,and the methodologies for detecting interactions are imperfect.To address these...Although genome-wide association studies are widely used to mine genes for quantitative traits,the effects to be estimated are confounded,and the methodologies for detecting interactions are imperfect.To address these issues,the mixed model proposed here first estimates the genotypic effects for AA,Aa,and aa,and the genotypic polygenic background replaces additive and dominance polygenic backgrounds.Then,the estimated genotypic effects are partitioned into additive and dominance effects using a one-way analysis of variance model.This strategy was further expanded to cover QTN-by-environment interactions(QEIs)and QTN-by-QTN interactions(QQIs)using the same mixed-model framework.Thus,a three-variance-component mixed model was integrated with our multi-locus random-SNP-effect mixed linear model(mrMLM)method to establish a new methodological framework,3VmrMLM,that detects all types of loci and estimates their effects.In Monte Carlo studies,3VmrMLM correctly detected all types of loci and almost unbiasedly estimated their effects,with high powers and accuracies and a low false positive rate.In re-analyses of 10 traits in 1439 rice hybrids,detection of 269 known genes,45 known gene-by-environment interactions,and 20 known gene-by-gene interactions strongly validated 3VmrMLM.Further analyses of known genes showed more small(67.49%),minor-allele-frequency(35.52%),and pleiotropic(30.54%)genes,with higher repeatability across datasets(54.36%)and more dominance loci.In addition,a heteroscedasticity mixed model in multiple environments and dimension reduction methods in quite a number of environments were developed to detect QEIs,and variable selection under a polygenic background was proposed for QQI detection.This study provides a new approach for revealing the genetic architecture of quantitative traits.展开更多
Most modern wheat cultivars were selected on the basis of yield-related indices measured under optimal fertilizer and irrigation inputs.With climate change,land degradation and salinity caused by sea water encroachmen...Most modern wheat cultivars were selected on the basis of yield-related indices measured under optimal fertilizer and irrigation inputs.With climate change,land degradation and salinity caused by sea water encroachment,wheat is increasingly subjected to environmental stress.Moreover,expanding urbanization increasingly encroaches upon prime agricultural land in countries like China,and alternative cropping areas must be found.Some of these areas have moderate constraining factors,such as salinity.Therefore,it is important to investigate whether current genetic materials and breeding procedures are maintaining adequate variability to address future problems caused by abiotic stress.In this study,a panel of 307 wheat accessions,including local landraces,exotic cultivars used in Chinese breeding programs and Chinese cultivars released during different periods since1940,were subjected to a genome-wide association study to dissect the genetic basis of salinity tolerance.Both marker-based and pedigree-based kinship analyses revealed that favorable haplotypes were introduced in some exotic cultivars as well as a limited number of Chinese landraces from the 1940 s.However,improvements in salinity tolerance during modern breeding are not as obvious as that of yield.To broaden genetic diversity for increasing salt tolerance,there is a need to refocus attention on local landraces that have high degrees of salinity tolerance and carry rare favorable alleles that have not been exploited in breeding.展开更多
Previous studies have reported that some important loci are missed in single-locus genome-wide association studies(GWAS),especially because of the large phenotypic error in field experiments.To solve this issue,multi-...Previous studies have reported that some important loci are missed in single-locus genome-wide association studies(GWAS),especially because of the large phenotypic error in field experiments.To solve this issue,multi-locus GWAS methods have been recommended.However,only a few software packages for multi-locus GWAS are available.Therefore,we developed an R software named mr MLM v4.0.2.This software integrates mr MLM,FASTmr MLM,FASTmr EMMA,p LARm EB,p KWm EB,and ISIS EM-BLASSO methods developed by our lab.There are four components in mr MLM v4.0.2,including dataset input,parameter setting,software running,and result output.The fread function in data.table is used to quickly read datasets,especially big datasets,and the do Parallel package is used to conduct parallel computation using multiple CPUs.In addition,the graphical user interface software mr MLM.GUI v4.0.2,built upon Shiny,is also available.To confirm the correctness of the aforementioned programs,all the methods in mr MLM v4.0.2 and three widely-used methods were used to analyze real and simulated datasets.The results confirm the superior performance of mr MLM v4.0.2 to other methods currently available.False positive rates are effectively controlled,albeit with a less stringent significance threshold.mr MLM v4.0.2 is publicly available at Bio Code(https://bigd.big.ac.cn/biocode/tools/BT007077)or R(https://cran.r-project.org/web/packages/mr MLM.GUI/index.html)as an open-source software.展开更多
The plant hormone abscisic acid(ABA)is crucial for plant seed germination and abiotic stress tolerance.However,the association between ABA sensitivity and plant abiotic stress tolerance remains largely unknown.In this...The plant hormone abscisic acid(ABA)is crucial for plant seed germination and abiotic stress tolerance.However,the association between ABA sensitivity and plant abiotic stress tolerance remains largely unknown.In this study,436 rice accessions were assessed for their sensitivity to ABA during seed germination.The considerable diversity in ABA sensitivity among rice germplasm accessions was primarily reflected by the differentiation between the Xian(indica)and Geng(japonica)subspecies and between the upland-Geng and lowland-Geng ecotypes.The upland-Geng accessions were most sensitive to ABA.Genome-wide association analyses identified four major quantitative trait loci containing21 candidate genes associated with ABA sensitivity of which a basic helix-loop-helix transcription factor gene,OsbHLH38,was the most important for ABA sensitivity.Comprehensive functional analyses using knockout and overexpression transgenic lines revealed that OsbHLH38 expression was responsive to multiple abiotic stresses.Overexpression of OsbHLH38 increased seedling salt tolerance,while knockout of OsbHLH38 increased sensitivity to salt stress.A salt-responsive transcription factor,OsDREB2A,interacted with OsbHLH38 and was directly regulated by OsbHLH38.Moreover,OsbHLH38 affected rice abiotic stress tolerance by mediating the expression of a large set of transporter genes of phytohormones,transcription factor genes,and many downstream genes with diverse functions,including photosynthesis,redox homeostasis,and abiotic stress responsiveness.These results demonstrated that OsbHLH38 is a key regulator in plant abiotic stress tolerance.展开更多
Vitamin E,consisting of tocopherols and tocotrienols,serves as a lipid-soluble antioxidant in sweet corn kernels,providing nutrients to both plants and humans.Though the key genes involved in the vitamin E biosynthesi...Vitamin E,consisting of tocopherols and tocotrienols,serves as a lipid-soluble antioxidant in sweet corn kernels,providing nutrients to both plants and humans.Though the key genes involved in the vitamin E biosynthesis pathway have been identified in plants,the genetic architecture of vitamin E content in sweet corn kernels remains largely unclear.In the present study,an association panel of 204 inbred lines of sweet corn was constructed.Seven compounds of vitamin E were quantified in sweet corn kernels at 28 days after pollination.A total of 119 loci for vitamin E were identified using a genome-wide association study based on genotyping by sequencing,and a genetic network of vitamin E was constructed.Candidate genes identified were involved mainly in RNA regulation and protein metabolism.The known gene ZmVTE4,encodingγ-tocopherol methyltransferase,was significantly associated with four traits(α-tocopherol,α-tocotrienol,theα/γ-tocopherol ratio,and theα/γ-tocotrienol ratio).The effects of two causative markers on ZmVTE4 were validated by haplotype analysis.Finally,two elite cultivars(Yuetian 9 and Yuetian 22)with a 4.5-fold increase in the sum ofα-andγ-tocopherols were developed by marker-assisted selection,demonstrating the successful biofortification of sweet corn.Three genes(DAHPS,ADT2,and cmu2)involved in chorismate and tyrosine synthesis were significantly associated with theα/γ-tocotrienol ratio.These results shed light on the genetic architecture of vitamin E and may accelerate the nutritional improvement of sweet corn.展开更多
Glucosinolates(GSLs) and their hydrolytic products contribute to the quality traits of rapeseed flowering stalk tissues, such as taste, flavor and anticarcinogenic properties(Glucoraphanin). However, little is known a...Glucosinolates(GSLs) and their hydrolytic products contribute to the quality traits of rapeseed flowering stalk tissues, such as taste, flavor and anticarcinogenic properties(Glucoraphanin). However, little is known about the genetic mechanisms of GSL accumulation in rapeseed flowering stalks. In this study, the variation and genetic architecture of GSL metabolites in flowering stalk tissues were investigated for the first time among a panel of 107 accessions. All GSL compounds exhibited continuous and wide variations in the present population. Progoitrin,glucobrassicanapin and gluconapin were the most abundant GSL compounds. Five quantitative trait loci(QTL) significantly associated with three GSL compounds were identified by genome-wide association study. GRA_C04 was under selected during modern breeding, in which the ratio of lower GSL haplotype(HAP2) in the accessions bred before 1990(52.56%) was significantly lower than that after 1990(78.95%). Four candidate genes, BnaA01. SOT16, BnaA06. SOT17, Bna A06. MYB51a, and Bna A06. MYB51b, were identified in the GTL_A01 and 4OH_A06 regions.These findings provide new insights into GSL biosynthesis in flowering stalk tissues and facilitate quality improvement in rapeseed flowering stalks.展开更多
Rice grain oil is a valuable nutrient source.However,the genetic basis of oil biosynthesis in rice grains remains unclear.In this study,we performed a genome-wide association study on oil composition and oil concentra...Rice grain oil is a valuable nutrient source.However,the genetic basis of oil biosynthesis in rice grains remains unclear.In this study,we performed a genome-wide association study on oil composition and oil concentration in a diverse panel of 533 cultivated rice accessions.High variation for 11 oil-related traits was observed,and the oil composition of rice grains showed differentiation among the subpopulations.We identified 46 loci that are significantly associated with grain oil concentration or composition,16 of which were detected in three recombinant inbred line populations.Twenty-six candidate genes encoding enzymes involved in oil metabolism were identified from these 46 loci,four of which(PAL6,LIN6,MYR2,and ARA6)were found to contribute to natural variation in oil composition and to show differentiation among the subpopulations.Interestingly,population genetic analyses revealed that specific haplotypes of PAL6 and LIN6 have been selected in japonica rice.Based on these results,we propose a possible oil biosynthetic pathway in rice grains.Collectively,our results provide new insights into the genetic basis of oil biosynthesis in rice grains and can facilitate marker-based breeding of rice varieties with enhanced oil and grain quality.展开更多
Genome-wide association studies （GWASs） efficiently identify genetic loci controlling traits at a relatively high resolution. In this study, variations in major early-maturation traits, including seedling period （S...Genome-wide association studies （GWASs） efficiently identify genetic loci controlling traits at a relatively high resolution. In this study, variations in major early-maturation traits, including seedling period （SP）, bud period （BP）, flower and boll period （FBP）, and growth period （GP）, of 169 upland cotton accessions were investigated, and a GWAS of early maturation was performed based on a CottonSNPSoK array. A total of 49,650 high-quality single-nucleotide polymorphisms （SNPs） were screened, and 29 significant SNPs located on chromosomes A6, A7, A8, D% D2, and D9, were repeatedly identified as associated with early-maturation traits, in at least two environments or two algorithms. Of these 29 significant SNPs, I, 12, 11, and 5 were related to SP, BP, FBP, and GP, respectively. Six peak SNPs, TM47967,TM13732, TM2o937, TM28428, TM5o283, and TM72552, exhibited phenotypic contributions of approximately lo%, which could allow them to be used for marker-assisted selection. One of these, TM72552, as well as four other SNPs, TM72554, TM72555, TM72558, and TM72559, corresponded to the quantitative trait loci previously reported. In total, 274 candidate genes were identified from the genome sequences of upland cotton and were categorized based on their functional annotations. Finally, our studies identified Gh_DoIGo34o and Gh_DoIGo34~ as potential candidate genes for improving cotton early maturity.展开更多
Wheat(Triticum aestivum)is among the most important staple crops for safeguarding the food security of the growing world population.To bridge the gap between genebank diversity and breeding programs,we developed an ad...Wheat(Triticum aestivum)is among the most important staple crops for safeguarding the food security of the growing world population.To bridge the gap between genebank diversity and breeding programs,we developed an advanced backcross-nested association mapping plus inter-crossed population(AB-NAMIC)by crossing three popular wheat cultivars as recurrent founders to 20 germplasm lines from a mini core collection.Selective backcrossing combined with selection against undesirable traits and extensive crossing within and between sub-populations created new opportunities to detect unknown genes and increase the frequency of beneficial alleles in the AB-NAMIC population.We performed phenotyping of 590 AB-NAMIC lines and a natural panel of 476 cultivars for six consecutive growing seasons and genotyped these 1066 lines with a 660K SNP array.Genome-wide association studies of both panels for plant development and yield traits demonstrated improved power to detect rare alleles and loci with medium genetic effects in AB-NAMIC.Notably,genome-wide association studies in AB-NAMIC detected the candidate gene TaSWEET6-7B(TraesCS7B03G1216700),which has high homology to the rice SWEET6b gene and exerts strong effects on adaptation and yield traits.The commercial release of two derived AB-NAMIC lines attests to its direct applicability in wheat improvement.Valuable information on genome-wide association studymapping,candidate genes,and their haplotypes for breeding traits are available through WheatGAB.Our research provides an excellent framework for fast-tracking exploration and accumulation of beneficial alleles stored in genebanks.展开更多
Marker-assisted selection(MAS)and genomic selection(GS)breeding have greatly improved the efficiency of rice breeding.Due to the influences of epistasis and gene pleiotropy,ensuring the actual breeding effect of MAS a...Marker-assisted selection(MAS)and genomic selection(GS)breeding have greatly improved the efficiency of rice breeding.Due to the influences of epistasis and gene pleiotropy,ensuring the actual breeding effect of MAS and GS is still a difficult challenge to overcome.In this study,113 indica rice varieties(V)and their 565 testcross hybrids(TC)were used as the materials to investigate the genetic basis of 12 quality traits and nine agronomic traits.The original traits and general combining ability of the parents,as well as the original traits and midparent heterosis of TC,were subjected to genome-wide association analysis.In total,381 primary significantly associated loci(SAL)and 1,759 secondary SALs that had epistatic interactions with these primary SALs were detected.Among these loci,322 candidate genes located within or nearby the SALs were screened,204 of which were cloned genes.A total of 39 MAS molecular modules that are beneficial for trait improvement were identified by pyramiding the superior haplotypes of candidate genes and desirable epistatic alleles of the secondary SALs.All the SALs were used to construct genetic networks,in which 91 pleiotropic loci were investigated.Additionally,we estimated the accuracy of genomic prediction in the parent V and TC by incorporating either no SALs,primary SALs,secondary SALs or epistatic effect SALs as covariates.Although the prediction accuracies of the four models were generally not significantly different in the TC dataset,the incorporation of primary SALs,secondary SALs,and epistatic effect SALs significantly improved the prediction accuracies of 5(26%),3(16%),and 11(58%)traits in the V dataset,respectively.These results suggested that SALs and epistatic effect SALs identified based on an additive genotype can provide considerable predictive power for the parental lines.They also provide insights into the genetic basis of complex traits and valuable information for molecular breeding in rice.展开更多
AIM: To identify genes associated with gastric pre-cancerous lesions in Helicobacter pylori (H. pylori )susceptible ethnic Malays. METHODS: Twenty-three Malay subjects with H. pylori infection and gastric precancerous...AIM: To identify genes associated with gastric pre-cancerous lesions in Helicobacter pylori (H. pylori )susceptible ethnic Malays. METHODS: Twenty-three Malay subjects with H. pylori infection and gastric precancerous lesions identified during endoscopy were included as "cases". Thirtyseven Malay subjects who were H. pylori negative and had no precancerous lesions were included as "controls". Venous blood was collected for genotyping with Affymetrix 50K Xba1 kit. Genotypes with call rates < 90% for autosomal single nucleotide polymorphisms (SNPs) were excluded. For each precancerous lesion, associated SNPs were identified from Manhattan plots, and only SNPs with a χ2 P value < 0.05 and Hardy Weinberg Equilibrium P value > 0.5 was considered as significant markers. RESULTS: Of the 23 H. pylori -positive subjects recruited, one sample was excluded from further analysis due to a low genotyping call rate. Of the 22 H. pylori positive samples, atrophic gastritis only was present in 50.0%, complete intestinal metaplasia was present in 18.25%, both incomplete intestinal metaplasia and dysplasia was present in 22.7%, and dysplasia only was present in 9.1%. SNPs rs9315542 (UFM1 gene), rs6878265 (THBS4 gene), rs1042194 (CYP2C19 gene) and rs10505799 (MGST1 gene) were significantly associated with atrophic gastritis, complete intestinal metaplasia, incomplete metaplasia with foci of dysplasia and dysplasia, respectively. Allele frequencies in "cases" vs "controls" for rs9315542, rs6878265, rs1042194 and rs10505799 were 0.4 vs 0.06, 0.6 vs 0.01, 0.6 vs 0.01 and 0.5 vs 0.02, respectively. CONCLUSION: Genetic variants possibly related to gastric precancerous lesions in ethnic Malays susceptible to H. pylori infection were identified for testing in subsequent trials.展开更多
文摘在过去的5年中,全基因组关联研究(Genome-wide association study,GWAS)方法已被证明是研究复杂疾病和性状遗传易感变异的一种有效手段。目前,各国科学家在多种复杂疾病和性状中开展了大量的GWAS,对肿瘤、糖尿病、心脏病、神经精神疾病、自身免疫及免疫相关疾病等复杂疾病以及一些常见性状(如身高、体重、血脂、色素等)的遗传易感基因研究取得了重大成果。截止到2010年9月11日,运用GWAS开展了对近200种复杂疾病/性状的研究,发现了3000多个疾病相关的遗传变异。文章就GWAS的发展及其在复杂疾病/性状中的应用做一综述。
文摘Type 2 diabetes mellitus(T2DM) is a complex disease in which both genetic and environmental factors interact in determining impaired β-cell insulin secretion and peripheral insulin resistance. Insulin resistance in muscle, liver and fat is a prominent feature of most patients with T2DM and obesity, resulting in a reduced response of these tissues to insulin. Considerable evidence has been accumulated to indicate that heredity is a major determinant of insulin resistance and T2DM. It is believed that, among individuals destined to develop T2DM, hyperinsulinemia is the mechanism by which the pancreatic β-cell initially compensates for deteriorating peripheral insulin sensitivity, thus ensuring normal glucose tolerance. Most of these people will develop T2DM when β-cells fail to compensate. Despite the progress achieved in this field in recent years, the genetic causes of insulin resistance and T2DM remain elusive.Candidate gene association, linkage and genome-wide association studies have highlighted the role of genetic factors in the development of T2DM. Using these strategies, a large number of variants have been identified in many of these genes, most of which may influence both hepatic and peripheral insulin resistance, adipogenesis and β-cell mass and function. Recently, a new gene has been identified by our research group, the HMGA1 gene, whose loss of function can greatly raise the risk of developing T2DM in humans and mice. Functional genetic variants of the HMGA1 gene have been associated with insulin resistance syndromes among white Europeans, Chinese individuals and Americans of Hispanic ancestry. These findings may represent new ways to improve or even prevent T2DM.
基金the National Key Research and Development Plan(2016YFD0101005,2016YFD0100201,and 2016YFD0100304)the National Natural Science Foundation of China(31871705 and 31422041)the Agricultural Science and Technology Innovation Program of Chinese Academy of Agricultural Sciences,and the Central Public-Interest Scientific Institution Basal Research Fund(Y2016JC13).
文摘Improved soybean cultivars have been adapted to grow at a wide range of latitudes,enabling expansion of cultivation worldwide.However,the genetic basis of this broad adaptation is still not clear.Here,we report the identification of GmPRR3b as a major flowering time regulatory gene that has been selected during domestication and genetic improvement for geographic expansion.Through a genome-wide association study of a diverse soybean landrace panel consisting of 279 accessions,we identified 16 candidate quantitative loci associated with flowering time and maturity time.The strongest signal resides in the known flowering gene E2,verifying the effectiveness of our approach.We detected strong signals associated with both flowering and maturity time in a genomic region containing GmPRR3b.Haplotype analysis revealed that GmPRR3bH6 is the major form of GmPRR3b that has been utilized during recent breeding of modern cultivars.mRNA profiling analysis showed that GmPRR3bH6 displays rhythmic and photoperiod-dependent expression and is preferentially induced under long-day conditions.Overexpression of GmPRR3bH6 increased main stem node number and yield,while knockout of GmPRR3bH6 using CRISPR/Cas9 technology delayed growth and the floral transition.GmPRR3bH6 appears to act as a transcriptional repressor of multiple predicted circadian clock genes,including GmCCAIa,which directly upregulates J/GmELF3a to modulate flowering time.The causal SNP(Chr12:5520945)likely endows GmPRR3bH6 a moderate but appropriate level of activity,leading to early flowering and vigorous growth traits preferentially selected during broad adaptation of landraces and improvement of cultivars.
基金supported by the Chinese Academy of Sciences “Strategic Priority Research Program” fund (XDA08020302)grants from State Key Laboratory of Plant Genomics。
文摘Genotyping and phenotyping large natural populations provide opportunities for population genomic analysis and genome-wide association studies(GWAS). Several rice populations have been re-sequenced in the past decade;however, many major Chinese rice cultivars were not included in these studies. Here, we report large-scale genomic and phenotypic datasets for a collection mainly comprised of 1,275 rice accessions of widely planted cultivars and parental hybrid rice lines from China. The population was divided into three indica/Xian and three japonica/Geng phylogenetic subgroups that correlate strongly with their geographic or breeding origins. We acquired a total of 146 phenotypic datasets for 29 agronomic traits under multi-environments for different subpopulations. With GWAS, we identified a total of 143 significant association loci, including three newly identified candidate genes or alleles that control heading date or amylose content. Our genotypic analysis of agronomically important genes in the population revealed that many favorable alleles are underused in elite accessions, suggesting they may be used to provide improvements in future breeding efforts. Our study provides useful resources for rice genetics research and breeding.
文摘The clinical outcome of hepatitis B virus(HBV) infection depends on the success or failure of the immune responses to HBV,and varies widely among individuals,ranging from asymptomatic self-limited infection,inactive carrier state,chronic hepatitis,cirrhosis,hepatocellular carcinoma,to liver failure,depending on the success or failure of immune response to HBV.Genome-wide association studies(GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits.In this review,we discuss GWAS for persistence of HBV infection,antibody response to hepatitis B vaccine,and HBV-related advanced liver diseases.HBV persistence is associated with multiple genes with diverse roles in immune mechanisms.The strongest associations are found within the classical human leukocyte antigen(HLA) genes,highlighting the central role of antigen presentation in the immune response to HBV.Associated variants affect both epitope binding specificities and expression levels of HLA molecules.Several other susceptibility genes regulate the magnitude of adaptive immune responses,determining immunity vs tolerance.HBV persistence and nonresponse to vaccine share the same risk variants,implying overlapping genetic bases.On the other hand,the risk variants for HBV-related advanced liver diseases are largely different,suggesting different host-virus dynamics in acute vs chronic HBV infections.The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.
基金supported by the Ministry of Science and Technology of China (2015 BAD02B01)
文摘Excess salinity is a natural stress that causes crop yield losses worldwide. The genetic bases of maize salt tolerance remain largely unknown. Here we investigated the survival rates of 445 maize natural accessions after salt treatments. A skewed distribution of the salttolerant phenotypes was observed in this population.Genome-wide association studies(GWAS) revealed 57 loci significantly associated with salt tolerance. Forty-nine candidate genes were detected from these loci. About10% of these genes were co-localized with loci from QTL mapping. Forty four percent of the candidate genes were involved in stress responses, ABA signaling,stomata division, DNA binding/transcription regulation and auxin signaling, suggesting that they are key genetic mechanisms of maize salt tolerance. Transgenic studies showed that two genes, the salt-tolerance-associatedgene 4(SAG4, GRMZM2 G077295) and SAG6(GRMZM2 G106056), which encode a protein transport protein and the double-strand break repair protein MRE11,respectively, had positive roles in plant salt tolerance,and their salt-tolerant haplotypes were revealed. The genes we identified in this study provide a list of candidate targets for further study of maize salt tolerance, and of genetic markers and materials that may be used for breeding salt-tolerance in maize.
基金supported by the National Natural Science Foundation of China(32070557 and 31871242)the Fundamental Research Funds for the Central Universities(2662020ZKPY017)+1 种基金the Huazhong Agricultural University Scientific&Technological Self-Innovation Foundation(2014RC020)the State Key Laboratory of Cotton Biology Open Fund(CB2021B01).
文摘Although genome-wide association studies are widely used to mine genes for quantitative traits,the effects to be estimated are confounded,and the methodologies for detecting interactions are imperfect.To address these issues,the mixed model proposed here first estimates the genotypic effects for AA,Aa,and aa,and the genotypic polygenic background replaces additive and dominance polygenic backgrounds.Then,the estimated genotypic effects are partitioned into additive and dominance effects using a one-way analysis of variance model.This strategy was further expanded to cover QTN-by-environment interactions(QEIs)and QTN-by-QTN interactions(QQIs)using the same mixed-model framework.Thus,a three-variance-component mixed model was integrated with our multi-locus random-SNP-effect mixed linear model(mrMLM)method to establish a new methodological framework,3VmrMLM,that detects all types of loci and estimates their effects.In Monte Carlo studies,3VmrMLM correctly detected all types of loci and almost unbiasedly estimated their effects,with high powers and accuracies and a low false positive rate.In re-analyses of 10 traits in 1439 rice hybrids,detection of 269 known genes,45 known gene-by-environment interactions,and 20 known gene-by-gene interactions strongly validated 3VmrMLM.Further analyses of known genes showed more small(67.49%),minor-allele-frequency(35.52%),and pleiotropic(30.54%)genes,with higher repeatability across datasets(54.36%)and more dominance loci.In addition,a heteroscedasticity mixed model in multiple environments and dimension reduction methods in quite a number of environments were developed to detect QEIs,and variable selection under a polygenic background was proposed for QQI detection.This study provides a new approach for revealing the genetic architecture of quantitative traits.
基金financially supported by the National Youth Foundation of China(31901494,31601306,and 31901869)the National Natural Science Foundation of China(31971890)+1 种基金supported by Young Elite Scientists Sponsorship Program of China Association for Science and Technology(2017QNRC001)the Natural Science Fund of Jiangsu Province,China(BK20161092)。
文摘Most modern wheat cultivars were selected on the basis of yield-related indices measured under optimal fertilizer and irrigation inputs.With climate change,land degradation and salinity caused by sea water encroachment,wheat is increasingly subjected to environmental stress.Moreover,expanding urbanization increasingly encroaches upon prime agricultural land in countries like China,and alternative cropping areas must be found.Some of these areas have moderate constraining factors,such as salinity.Therefore,it is important to investigate whether current genetic materials and breeding procedures are maintaining adequate variability to address future problems caused by abiotic stress.In this study,a panel of 307 wheat accessions,including local landraces,exotic cultivars used in Chinese breeding programs and Chinese cultivars released during different periods since1940,were subjected to a genome-wide association study to dissect the genetic basis of salinity tolerance.Both marker-based and pedigree-based kinship analyses revealed that favorable haplotypes were introduced in some exotic cultivars as well as a limited number of Chinese landraces from the 1940 s.However,improvements in salinity tolerance during modern breeding are not as obvious as that of yield.To broaden genetic diversity for increasing salt tolerance,there is a need to refocus attention on local landraces that have high degrees of salinity tolerance and carry rare favorable alleles that have not been exploited in breeding.
基金supported by the National Natural Science Foundation of China(Grant Nos.31871242,U1602261,31701071,21873034,and 31571268)the Huazhong Agricultural University Scientific&Technological Self-innovation Foundation,China(Grant No.2014RC020)the State Key Laboratory of Cotton Biology Open Fund,China(Grant No.CB2019B01)
文摘Previous studies have reported that some important loci are missed in single-locus genome-wide association studies(GWAS),especially because of the large phenotypic error in field experiments.To solve this issue,multi-locus GWAS methods have been recommended.However,only a few software packages for multi-locus GWAS are available.Therefore,we developed an R software named mr MLM v4.0.2.This software integrates mr MLM,FASTmr MLM,FASTmr EMMA,p LARm EB,p KWm EB,and ISIS EM-BLASSO methods developed by our lab.There are four components in mr MLM v4.0.2,including dataset input,parameter setting,software running,and result output.The fread function in data.table is used to quickly read datasets,especially big datasets,and the do Parallel package is used to conduct parallel computation using multiple CPUs.In addition,the graphical user interface software mr MLM.GUI v4.0.2,built upon Shiny,is also available.To confirm the correctness of the aforementioned programs,all the methods in mr MLM v4.0.2 and three widely-used methods were used to analyze real and simulated datasets.The results confirm the superior performance of mr MLM v4.0.2 to other methods currently available.False positive rates are effectively controlled,albeit with a less stringent significance threshold.mr MLM v4.0.2 is publicly available at Bio Code(https://bigd.big.ac.cn/biocode/tools/BT007077)or R(https://cran.r-project.org/web/packages/mr MLM.GUI/index.html)as an open-source software.
基金supported by the National Key Research and Development Program of China(2020YFE0202300)the National Natural Science Foundation of China(31971928)+2 种基金the Hainan Yazhou Bay Seed Lab Project(B23CJ0208,B21HJ0223,and B21HJ0508)the CAAS Innovative Team Award(to BYF and WSW)the National High-level Personnel of Special Support Program(to WSW)。
文摘The plant hormone abscisic acid(ABA)is crucial for plant seed germination and abiotic stress tolerance.However,the association between ABA sensitivity and plant abiotic stress tolerance remains largely unknown.In this study,436 rice accessions were assessed for their sensitivity to ABA during seed germination.The considerable diversity in ABA sensitivity among rice germplasm accessions was primarily reflected by the differentiation between the Xian(indica)and Geng(japonica)subspecies and between the upland-Geng and lowland-Geng ecotypes.The upland-Geng accessions were most sensitive to ABA.Genome-wide association analyses identified four major quantitative trait loci containing21 candidate genes associated with ABA sensitivity of which a basic helix-loop-helix transcription factor gene,OsbHLH38,was the most important for ABA sensitivity.Comprehensive functional analyses using knockout and overexpression transgenic lines revealed that OsbHLH38 expression was responsive to multiple abiotic stresses.Overexpression of OsbHLH38 increased seedling salt tolerance,while knockout of OsbHLH38 increased sensitivity to salt stress.A salt-responsive transcription factor,OsDREB2A,interacted with OsbHLH38 and was directly regulated by OsbHLH38.Moreover,OsbHLH38 affected rice abiotic stress tolerance by mediating the expression of a large set of transporter genes of phytohormones,transcription factor genes,and many downstream genes with diverse functions,including photosynthesis,redox homeostasis,and abiotic stress responsiveness.These results demonstrated that OsbHLH38 is a key regulator in plant abiotic stress tolerance.
基金the National Natural Science Foundation of China(31601309)Science and Technology Planning Project of Guangdong Province(2016B020233004,2015A020209063,2017B090907023)+2 种基金Science and Technology Planning Project of Guangzhou(201804020081)Agricultural Development and Rural Work Special Project-Modern Seed Industry Enhancement Project of Guangdong(201788)the Excellent PhD Program of Guangdong Academy of Agricultural Sciences(2017).
文摘Vitamin E,consisting of tocopherols and tocotrienols,serves as a lipid-soluble antioxidant in sweet corn kernels,providing nutrients to both plants and humans.Though the key genes involved in the vitamin E biosynthesis pathway have been identified in plants,the genetic architecture of vitamin E content in sweet corn kernels remains largely unclear.In the present study,an association panel of 204 inbred lines of sweet corn was constructed.Seven compounds of vitamin E were quantified in sweet corn kernels at 28 days after pollination.A total of 119 loci for vitamin E were identified using a genome-wide association study based on genotyping by sequencing,and a genetic network of vitamin E was constructed.Candidate genes identified were involved mainly in RNA regulation and protein metabolism.The known gene ZmVTE4,encodingγ-tocopherol methyltransferase,was significantly associated with four traits(α-tocopherol,α-tocotrienol,theα/γ-tocopherol ratio,and theα/γ-tocotrienol ratio).The effects of two causative markers on ZmVTE4 were validated by haplotype analysis.Finally,two elite cultivars(Yuetian 9 and Yuetian 22)with a 4.5-fold increase in the sum ofα-andγ-tocopherols were developed by marker-assisted selection,demonstrating the successful biofortification of sweet corn.Three genes(DAHPS,ADT2,and cmu2)involved in chorismate and tyrosine synthesis were significantly associated with theα/γ-tocotrienol ratio.These results shed light on the genetic architecture of vitamin E and may accelerate the nutritional improvement of sweet corn.
基金supported by the Key Research and Development project of Hubei Province (Grant Nos. 2020BBB083, 2021BBA097 and 2021BBA102)the National Key Research and Development Program of China (Grant No. 2016YFD0100202)。
文摘Glucosinolates(GSLs) and their hydrolytic products contribute to the quality traits of rapeseed flowering stalk tissues, such as taste, flavor and anticarcinogenic properties(Glucoraphanin). However, little is known about the genetic mechanisms of GSL accumulation in rapeseed flowering stalks. In this study, the variation and genetic architecture of GSL metabolites in flowering stalk tissues were investigated for the first time among a panel of 107 accessions. All GSL compounds exhibited continuous and wide variations in the present population. Progoitrin,glucobrassicanapin and gluconapin were the most abundant GSL compounds. Five quantitative trait loci(QTL) significantly associated with three GSL compounds were identified by genome-wide association study. GRA_C04 was under selected during modern breeding, in which the ratio of lower GSL haplotype(HAP2) in the accessions bred before 1990(52.56%) was significantly lower than that after 1990(78.95%). Four candidate genes, BnaA01. SOT16, BnaA06. SOT17, Bna A06. MYB51a, and Bna A06. MYB51b, were identified in the GTL_A01 and 4OH_A06 regions.These findings provide new insights into GSL biosynthesis in flowering stalk tissues and facilitate quality improvement in rapeseed flowering stalks.
基金This work was supported by grants from the Ministry of Science and Technology(Grant 2016YFD0100501)the National Program on R&D of Transgenic Plants(2016ZX08009004)+3 种基金the National Natural Science Foundation of China(91935303,31821005 and 32000378)the earmarked fund for the China Agricultural Research System(CARS-01-03)the Hubei province of Science and Technology(2020BBB051)the Postdoctoral Science Foundation of China(2017M622477).
文摘Rice grain oil is a valuable nutrient source.However,the genetic basis of oil biosynthesis in rice grains remains unclear.In this study,we performed a genome-wide association study on oil composition and oil concentration in a diverse panel of 533 cultivated rice accessions.High variation for 11 oil-related traits was observed,and the oil composition of rice grains showed differentiation among the subpopulations.We identified 46 loci that are significantly associated with grain oil concentration or composition,16 of which were detected in three recombinant inbred line populations.Twenty-six candidate genes encoding enzymes involved in oil metabolism were identified from these 46 loci,four of which(PAL6,LIN6,MYR2,and ARA6)were found to contribute to natural variation in oil composition and to show differentiation among the subpopulations.Interestingly,population genetic analyses revealed that specific haplotypes of PAL6 and LIN6 have been selected in japonica rice.Based on these results,we propose a possible oil biosynthetic pathway in rice grains.Collectively,our results provide new insights into the genetic basis of oil biosynthesis in rice grains and can facilitate marker-based breeding of rice varieties with enhanced oil and grain quality.
基金supported by the National Natural Science Foundation of China(31671743)the Innovative Talent Support Program of Science and Technology of the Henan Institute of Higher Learning(16HASTIT014)the Middle-aged or Young Leading Talent Project of Xinjiang Production and Construction Group(2016BC001)
文摘Genome-wide association studies （GWASs） efficiently identify genetic loci controlling traits at a relatively high resolution. In this study, variations in major early-maturation traits, including seedling period （SP）, bud period （BP）, flower and boll period （FBP）, and growth period （GP）, of 169 upland cotton accessions were investigated, and a GWAS of early maturation was performed based on a CottonSNPSoK array. A total of 49,650 high-quality single-nucleotide polymorphisms （SNPs） were screened, and 29 significant SNPs located on chromosomes A6, A7, A8, D% D2, and D9, were repeatedly identified as associated with early-maturation traits, in at least two environments or two algorithms. Of these 29 significant SNPs, I, 12, 11, and 5 were related to SP, BP, FBP, and GP, respectively. Six peak SNPs, TM47967,TM13732, TM2o937, TM28428, TM5o283, and TM72552, exhibited phenotypic contributions of approximately lo%, which could allow them to be used for marker-assisted selection. One of these, TM72552, as well as four other SNPs, TM72554, TM72555, TM72558, and TM72559, corresponded to the quantitative trait loci previously reported. In total, 274 candidate genes were identified from the genome sequences of upland cotton and were categorized based on their functional annotations. Finally, our studies identified Gh_DoIGo34o and Gh_DoIGo34~ as potential candidate genes for improving cotton early maturity.
基金supported by the National Key Research and Development Program of China(2022YFD1201503 and 2016YFD0100302)the National Major Agricultural Science and Technology Project(NK2022060101).
文摘Wheat(Triticum aestivum)is among the most important staple crops for safeguarding the food security of the growing world population.To bridge the gap between genebank diversity and breeding programs,we developed an advanced backcross-nested association mapping plus inter-crossed population(AB-NAMIC)by crossing three popular wheat cultivars as recurrent founders to 20 germplasm lines from a mini core collection.Selective backcrossing combined with selection against undesirable traits and extensive crossing within and between sub-populations created new opportunities to detect unknown genes and increase the frequency of beneficial alleles in the AB-NAMIC population.We performed phenotyping of 590 AB-NAMIC lines and a natural panel of 476 cultivars for six consecutive growing seasons and genotyped these 1066 lines with a 660K SNP array.Genome-wide association studies of both panels for plant development and yield traits demonstrated improved power to detect rare alleles and loci with medium genetic effects in AB-NAMIC.Notably,genome-wide association studies in AB-NAMIC detected the candidate gene TaSWEET6-7B(TraesCS7B03G1216700),which has high homology to the rice SWEET6b gene and exerts strong effects on adaptation and yield traits.The commercial release of two derived AB-NAMIC lines attests to its direct applicability in wheat improvement.Valuable information on genome-wide association studymapping,candidate genes,and their haplotypes for breeding traits are available through WheatGAB.Our research provides an excellent framework for fast-tracking exploration and accumulation of beneficial alleles stored in genebanks.
基金partially supported by the Science and Technology Innovation Program of Hunan Province,China(2023NK2001)the Hubei Key Laboratory of Food Crop Germplasm and Genetic Improvement,China(2022LZJJ08)+2 种基金the Special Funds for Construction of Innovative Provinces in Hunan Province,China(2021NK1011)the Natural Science Foundation of Hunan Province,China(2020JJ4039)the Key Research and Development Program of Hubei Province,China(2021BBA223)。
文摘Marker-assisted selection(MAS)and genomic selection(GS)breeding have greatly improved the efficiency of rice breeding.Due to the influences of epistasis and gene pleiotropy,ensuring the actual breeding effect of MAS and GS is still a difficult challenge to overcome.In this study,113 indica rice varieties(V)and their 565 testcross hybrids(TC)were used as the materials to investigate the genetic basis of 12 quality traits and nine agronomic traits.The original traits and general combining ability of the parents,as well as the original traits and midparent heterosis of TC,were subjected to genome-wide association analysis.In total,381 primary significantly associated loci(SAL)and 1,759 secondary SALs that had epistatic interactions with these primary SALs were detected.Among these loci,322 candidate genes located within or nearby the SALs were screened,204 of which were cloned genes.A total of 39 MAS molecular modules that are beneficial for trait improvement were identified by pyramiding the superior haplotypes of candidate genes and desirable epistatic alleles of the secondary SALs.All the SALs were used to construct genetic networks,in which 91 pleiotropic loci were investigated.Additionally,we estimated the accuracy of genomic prediction in the parent V and TC by incorporating either no SALs,primary SALs,secondary SALs or epistatic effect SALs as covariates.Although the prediction accuracies of the four models were generally not significantly different in the TC dataset,the incorporation of primary SALs,secondary SALs,and epistatic effect SALs significantly improved the prediction accuracies of 5(26%),3(16%),and 11(58%)traits in the V dataset,respectively.These results suggested that SALs and epistatic effect SALs identified based on an additive genotype can provide considerable predictive power for the parental lines.They also provide insights into the genetic basis of complex traits and valuable information for molecular breeding in rice.
基金Supported by Fundamental Research Grant Scheme(FRGS)203/PPSP/6171121,1001/PPSP/812016 and 1001/PPSP/8122022 of Universiti Sains MalaysiaThe National Science Foundation of China grants,No.30971577and No.31171218+5 种基金the Shanghai Rising-Star Program,No.11QA1407600the Science Foundation of the Chinese Academy of Sciences(CAS)(KSCX2-EW-Q-1-11KSCX2-EW-R-01-05KSCX2-EW-J-15-05)the support of the National Program for Top-notch Young Innovative Talentsthe support of K.C. Wong Education Foundation, Hong Kong
文摘AIM: To identify genes associated with gastric pre-cancerous lesions in Helicobacter pylori (H. pylori )susceptible ethnic Malays. METHODS: Twenty-three Malay subjects with H. pylori infection and gastric precancerous lesions identified during endoscopy were included as "cases". Thirtyseven Malay subjects who were H. pylori negative and had no precancerous lesions were included as "controls". Venous blood was collected for genotyping with Affymetrix 50K Xba1 kit. Genotypes with call rates < 90% for autosomal single nucleotide polymorphisms (SNPs) were excluded. For each precancerous lesion, associated SNPs were identified from Manhattan plots, and only SNPs with a χ2 P value < 0.05 and Hardy Weinberg Equilibrium P value > 0.5 was considered as significant markers. RESULTS: Of the 23 H. pylori -positive subjects recruited, one sample was excluded from further analysis due to a low genotyping call rate. Of the 22 H. pylori positive samples, atrophic gastritis only was present in 50.0%, complete intestinal metaplasia was present in 18.25%, both incomplete intestinal metaplasia and dysplasia was present in 22.7%, and dysplasia only was present in 9.1%. SNPs rs9315542 (UFM1 gene), rs6878265 (THBS4 gene), rs1042194 (CYP2C19 gene) and rs10505799 (MGST1 gene) were significantly associated with atrophic gastritis, complete intestinal metaplasia, incomplete metaplasia with foci of dysplasia and dysplasia, respectively. Allele frequencies in "cases" vs "controls" for rs9315542, rs6878265, rs1042194 and rs10505799 were 0.4 vs 0.06, 0.6 vs 0.01, 0.6 vs 0.01 and 0.5 vs 0.02, respectively. CONCLUSION: Genetic variants possibly related to gastric precancerous lesions in ethnic Malays susceptible to H. pylori infection were identified for testing in subsequent trials.
