Interaction detection in large-scale genetic asso- ciation studies has attracted intensive research interest, since many diseases have complex traits. Various approaches have been developed for finding significant gen...Interaction detection in large-scale genetic asso- ciation studies has attracted intensive research interest, since many diseases have complex traits. Various approaches have been developed for finding significant genetic interactions. In this article, we propose a novel framework SRMiner to detect interacting susceptible and protective genotype patterns. SR- Miner can discover not only probable combination of single nucleotide polymorphisms （SNPs） causing diseases but also the corresponding SNPs suppressing their pathogenic func- tions, which provides a better prospective to uncover the un- derlying relevance between genetic variants and complex dis- eases. We have performed extensive experiments on several real WeUcome Trust Case Control Consortium （WTCCC） datasets. We use the pathway-based and the protein-protein interaction （PPI） network-based evaluation methods to verify the discovered patterns. The results show that SRMiner successfully identifies many disease-related genes verified by the existing work. Furthermore, SRMiner can also infer some uncomfirmed but highly possible disease-related genes.展开更多
In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values w...In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values with a large numberof samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data,we developed a robust and user-friendly software platform with a series of tools for analysis in association study withhigh efficiency. The platform has been well evaluated by several sets of real data.展开更多
Objective To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease(NAFLD).Methods Literature from Web of Science,PubMed,and Embase between January 1...Objective To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease(NAFLD).Methods Literature from Web of Science,PubMed,and Embase between January 1980 and September 2022 was systematically searched.Meta-analyses of the genetic variants were conducted using at least five data sources.The epidemiologic credibility of the significant associations was graded using the Venice criteria.Results Based on literature screening,399 eligible studies were included,comprising 381 candidate gene association,16 genome-wide association,and 2 whole-exome sequencing studies.We identified 465 genetic variants in 173 genes in candidate gene association studies,and 25 genetic variants in 17 genes were included in the meta-analysis.The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD,with cumulative epidemiological evidence of an association graded as strong for two variants in two genes(HFE,TNF),moderate for four variants in three genes(TM6SF2,GCKR,and ADIPOQ),and weak for five variants in five genes(MBOAT7,PEMT,PNPLA3,LEPR,and MTHFR).Conclusion This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD,which may help understand the genetic architecture of NAFLD risk.展开更多
AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with ris...AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.展开更多
For lifetime non-smokers, lung cancer risk is mainly associated with inhalation exposure to air pollution. For the Chinese population, indoor air pollution due to solid fuel combustion has been the primary source of i...For lifetime non-smokers, lung cancer risk is mainly associated with inhalation exposure to air pollution. For the Chinese population, indoor air pollution due to solid fuel combustion has been the primary source of inhalation exposure for decades. Polycyclic aromatic hydrocarbons （PAHs） are the by-products of incomplete combustion.展开更多
Backgrounds: Although many disease-associated common variants have been discovered through genome-wide association studies, much of the genetic effects of complex diseases have not been explained. Population-based ass...Backgrounds: Although many disease-associated common variants have been discovered through genome-wide association studies, much of the genetic effects of complex diseases have not been explained. Population-based association studies are vulnerable to population stratification. A possible solution is to use family-based tests. However, if tests only estimate the genetic effect from the within-family variation to avoid population stratification, they may ignore the useful genetic information from between-family variation and lose power. Methods: We have developed an adaptive weighted sum test for family-based association studies. The new test uses data driven weights to combine two test statistics, and the weights measure the strength of population stratification. When population stratification is strong, the proposed test will automatically put more weight on one statistic derived from within-family variation to maintain robustness against spurious positives. On the other hand, when the effect of population stratification is relatively weak, the proposed test will automatically put more weight on the other statistic derived from both within-family and between-family variation to make use of both sources of genetic variation;and at the same time, the degrees of freedom of the test will be reduced and power of the test will be increased. Results: In our study, the proposed method achieves a higher power in most scenarios of linkage disequilibrium structure as well as Hap Map data from different genes under different population structures while still keeping its robustness against population stratification.展开更多
Schizophrenia（SCZ） is a complex and heterogeneous mental disorder that affects about 1% of global population. In recent years,considerable progress has been made in genetic studies of SCZ. A number of common variant...Schizophrenia（SCZ） is a complex and heterogeneous mental disorder that affects about 1% of global population. In recent years,considerable progress has been made in genetic studies of SCZ. A number of common variants with small effects and rare variants with relatively larger effects have been identifi ed. These variants include risk loci identifi ed by genome-wide association studies,rare copy-number variants identifi ed by comparative genomic analyses,and de novo mutations identified by high-throughput DNA sequencing. Collectively,they contribute to the heterogeneity of the disease. In this review,we update recent discoveries in the fi eld of SCZ genetics,and outline the perspectives of future directions.展开更多
Early-and late-onset narcolepsy constitutes two distinct diagnostic subgroups.However,it is not clear whether symptomology and genetic risk factors differ between early-and late-onset narcoleptics.This study compared ...Early-and late-onset narcolepsy constitutes two distinct diagnostic subgroups.However,it is not clear whether symptomology and genetic risk factors differ between early-and late-onset narcoleptics.This study compared clinical data and single-nucleotide polymorphisms(SNPs)between early-and late-onset patients in a large cohort of 899 Han Chinese narcolepsy patients.Blood,cerebrospinal fluid,and clinical data were prospectively collected from patients,and patients were genotyped for 40 previously reported narcolepsy risk-conferring SNPs.Genetic risk scores(GRSs),associations of five different sets of SNPs(GRS1–GRS5)with early-and late-onset narcolepsy,were evaluated using logistic regression and receiver operating characteristic curves.Mean sleep latency was significantly shorter in early-onset cases than in late-onset cases.Symptom severity was greater among late-onset patients,with higher rates of sleep paralysis,hypnagogic hallucinations,health-related quality of life impairment,and concurrent presentation with four or more symptoms.Hypocretin levels did not differ significantly between early-and late-onset cases.Only rs3181077(CCR1/CCR3)and rs9274477(HLA-DQB1)were more prevalent among early-onset cases.Only GRS1(26 SNPs;OR=1.513,95%CI:0.893–2.585;P<0.05)and GRS5(6 SNPs;OR=1.893,95%CI:1.204–2.993;P<0.05)were associated with early-onset narcolepsy,with areas under the receiver operating characteristic curves of 0.731 and 0.732,respectively.Neither GRS1 nor GRS5 included SNPs in HLA regions.Our results indicate that symptomology and genetic risk factors differ between early-and late-onset narcolepsy.This protocol was approved by the Institutional Review Board(IRB)Panels on Medical Human Subjects at Peking University People’s Hospital,China(approval No.Yuanlunshenlinyi 86)in October 2011.展开更多
The disease burden of diabetic retinopathy(DR)is tremendous around the world.While DR is correlated with hemoglobin A1c(HbA1c)and duration of diabetes,genetic differences likely account for variation in susceptibility...The disease burden of diabetic retinopathy(DR)is tremendous around the world.While DR is correlated with hemoglobin A1c(HbA1c)and duration of diabetes,genetic differences likely account for variation in susceptibility to DR.DR is a polygenic disorder with demonstrated heritability.However,linkage and admixture analyses,candidate gene association studies,and genome-wide association studies(GWAS)have not identified many loci for DR that can be consistently replicated.Larger,collaborative,multi-ethnic GWAS are needed to identify common variants with small effects.Rigorous defining of controls groups as patients with a long duration of diabetes without DR,and case groups as patients with severe DR will also aid in finding genes associated with DR.Replication in independent cohorts will be key to establishing associated loci for DR.Investigations of mitochondrial DNA and epigenetics in DR are ongoing.Whole exome sequencing presents new opportunities to identify rare variants that might be implicated in DR development.Continued research in the genetic epidemiology of DR is needed,with the potential to elucidate pathogenesis and treatment of an important disease.展开更多
Family-based tests of association between a genetic marker and a disease constitute a common design to dissect the genetic architecture of complex traits. The FBAT software is one of the most popular tools to perform ...Family-based tests of association between a genetic marker and a disease constitute a common design to dissect the genetic architecture of complex traits. The FBAT software is one of the most popular tools to perform such studies. However, researchers are also often interested in the genetic contribution to a more specific manifestation of the phenotype (e.g. severe vs. non-severe form) known as a secondary outcome. Here, what we demonstrate is the limited power of the classical formulation of the FBAT statistic to detect the effect of genetic variants that influence a secondary outcome, in particular when these variants also impact on the onset of the disease, the primary outcome. We prove that this loss of power is driven by an implicit hypothesis, and we propose a derivation of the original FBAT statistic, free from this implicit hypothesis. Finally, we demonstrate analytically that our new statistic is robust and more powerful than FBAT for the detection of association between a genetic variant and a secondary outcome.展开更多
Transmission disequilibrium tests (TDT) is a well-known case-parents family-based method to detect the association between genetic polymorphisms and a disease phenotype. Various extensions of the TDT have been develop...Transmission disequilibrium tests (TDT) is a well-known case-parents family-based method to detect the association between genetic polymorphisms and a disease phenotype. Various extensions of the TDT have been developed and widely applied in medical research. In this article, we introduced a simple simulation algorithm based on a transition model to generate general nuclear families rather than trios to simulate multiple tightly linked markers. The simulations show that the empirical distributions of the test statistics coincide with the expected distribution under the null hypothesis.展开更多
Recently,new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis.The four hits theory has been confirmed but several genetic wide association studies have allowed finding several g...Recently,new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis.The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease.All these new genes apply to each of the four hits.Additionally,new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis.The IgA treatment is also changed included the future possibilities.The treatment of the chronic kidney disease,associated with the nephropathy,is mandatory,since the beginning of the disease.The classical immunosuppressive agents have poor effect.The corticosteroids remain an important cornerstone in any phase of the disease.More effect is related to the treatment of B cells and plasma cells.In particular,in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents.Most of these studies are to date in phase II/III.Finally,new agents targeting complement are arising.These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.展开更多
<strong>Introduction:</strong> The goal of this study was to utilize physical characteristics instead of placing subjects in arbitrary diagnostic categories to test for associations with genetic variants. ...<strong>Introduction:</strong> The goal of this study was to utilize physical characteristics instead of placing subjects in arbitrary diagnostic categories to test for associations with genetic variants. <strong>Methods:</strong> Forty-four single nucleotide polymorphisms were tested for association with specific cephalometric measurements in thirty-nine University of Pittsburgh Dental Registry and DNA Repository orthodontic subjects. Cephalometric measurements included an evaluation of FMA, a Wits appraisal, and a Steiner’s ANB analysis. Genetic markers were genotyped using polymerase chain reaction and Taqman chemistry. Chi-square and Fischer’s exact tests (α = 0.05) were used in investigation of overrepresentation of marker alleles. Samples were divided into groups based upon having an FMA, Wits, or ANB measurement above or below the mean of the cohort studied. Secondary analysis was done for sex and ethnicity to determine their effect on FMA, Wits, or ANB. <strong>Results: </strong>An association between FMA measurements was discovered in the following genes: ACTN3, CASP4, ESR1, FGF13, KRT7, and PITX2. An association between Wits measurements was discovered in the following genes: ACTN2, BTBD11, CASP4, FGF3, and FGF10. No associations were found with ANB.<strong> Conclusions: </strong>Genetic markers in several genes at different loci may contribute to craniofacial deformities in humans. This approach of using physical measurements may be an advantage to placing patients in arbitrary diagnostic categories.展开更多
Background Genetic association studies on populations of European origin have identified the DCDC2 gene as a susceptibility locus for developmental dyslexia.Here,we sought to investigate the association of DCDC2 polym...Background Genetic association studies on populations of European origin have identified the DCDC2 gene as a susceptibility locus for developmental dyslexia.Here,we sought to investigate the association of DCDC2 polymorphisms with developmental dyslexia in children of Han Chinese origin.Methods We undertook a case-control genetic association study on 76 dyslexic children and 79 non-dyslexic matched controls.We isolated DNA from oral mucosal cell samples and genotyped two DCDC2 coding-sequence single nucleotide polymorphisms,rs2274305 and rs6456593,in each sample using SNaPshot single nucleotide extension.We compared the allele and genotype frequencies between the groups using the X2 test and analyzed the relationship between dyslexia and the polymorphism at both loci using unconditional logistic regression.We also predicted haplotypes and compared their frequencies between the two groups.Results The differences in the genotype distribution and the allelic genes of the two single nucleotide luci of the DCDC2 gene,rs2274305 and rs6456593,between the two dyslexic and non-dyslexic groups were statistically meaningless （P 〉0.05）.The differences in the haplotype distributions of the DCDC2 gene between the dyslexic and normal group were statistically meaningless （P 〉0.05）.Conclusion The DCDC2 gene may not be a susceptibility factor for developmental dyslexia among the Han Chinese.However,methodological issues may have prevented the detection of oositive associations.展开更多
Background Parkinson＇s disease （PD） is an autosomally inherited neurodegenerative disease in elderly people.The etiology of PD has long been thought to be associated with both genetic and environmental factors.To e...Background Parkinson＇s disease （PD） is an autosomally inherited neurodegenerative disease in elderly people.The etiology of PD has long been thought to be associated with both genetic and environmental factors.To explore potential genetic risk factors for PD in the northern Han Chinese population,we investigated three single nucleotide polymorphisms （SNPs） （rs4538475,rs11107 and rs12564040） in the BST1,PARK15 and PARK9 genes.Methods Genomic DNA from 215 PD patients and 212 matched controls was amplified in two independent PCR systems and subsequently genotyped by digestion with the endonuclease Pstl.Genetic parameter and association studies were carried out with SPSS 13.0 and PLINK 1.07 software.Results We could accurately detect all genotypes in the three loci with the PCR-RFLP or mismatched PCR-RFLP techniques.The observed heterozygosities of the rs4538475 and rs11107 loci in PD and control groups ranged from 0.460-0.481 and 0.410-0.441,in BST1,PARK15 respectively,while we detected no heterozygosity at the rs12564040 locus in PARK9.The similar distributions of genotypic frequency between both groups suggest that the three SNPs investigated in this study are unlikely to play roles as common risk factors or pathogenic mutations for PD in northern Han Chinese.Conclusion The SNPs investigated in the BST1,PARK15 and PARK9 genes associated with PD susceptibility are not associated with PD in the northern Han Chinese population.展开更多
Background Coordinated regulation of nutrient and inflammatory responses by six transmembrane epithelial antigen of prostate 4 （STEAP4） was essential for metabolic homeostasis. STEAP4 expression in human white adipo...Background Coordinated regulation of nutrient and inflammatory responses by six transmembrane epithelial antigen of prostate 4 （STEAP4） was essential for metabolic homeostasis. STEAP4 expression in human white adipose tissuewas associated with obesity. This study aimed to evaluate association between STEAP4 genetic polymorphisms and obesity in Uygur Chinese general population.Methods The functional regions of STEAP4 gene were sequenced in 96 Uygur with obesity （body mass index （BMI）〉30 kg/m2）. Representative variations were selected according to the function and linkage disequilibrium and genotyped in 1507 obesity （BMI ≥25 kg/m2） and 825 non-obesity control （BMI ＜25 kg/m2）, all of whom were selected from epidemiology study of obesity-related diseases during January to February 2007 among Uygur population in Hetian area of Xinjiang Uygur Autonomous Region.Results Fourteen novel and 6 known single nucleotide polymorphism （SNPs）, including 2 nonsynonymous SNPs （nsSNPs）, in the STEAP4 gene were identified. Of the 3 representative SNPs, the nsSNP rs1981529 （Gly75Asp, 224A/G）was significantly associated with obesity phenotype （additive P/Pc=0.001/0.006, dominant P/Pc=0.003/0.018, odds ratio （OR） and 95％ confidence interval （CI） adjusted for age, gender and drinking 0.755 （0.641-0.890） and 0.750（0.621-0.907）, respectively）. By the multiple linear regression analysis, the quantitative phenotypes of BMI （P/Pc=0.002/0.004） and waist circumference （P/Pc=0.004/0.008） were found to be significantly associated with the genotypes of rs1981529 （Gly75Asp, 224A/G） in Uygur general population, and effect size （beta value） of one allele G of rs1981529 （Gly75Asp, 224A/G） was-0.553 kg/m2 for BMI and -1.311 cm for waist circumference after controlling age,gender and drinking factors.Conclusions The present study shows an association of the common variation rs1981529 （Gly75Asp, 224A/G） in the STEAP4 gene with obesity in Uygur general population. Further studies should replicate the results using larger populations.展开更多
Background： Multiple sclerosis （MS） is a common central nervous system autoimmune disorder. Increasing number of genome-wide association study （GWAS） analyses hint that MS is strongly associated with genetics. Un...Background： Multiple sclerosis （MS） is a common central nervous system autoimmune disorder. Increasing number of genome-wide association study （GWAS） analyses hint that MS is strongly associated with genetics. Unfortunately, almost all the GWAS analyses were Caucasian population based. Numbers of risk loci might not be replicated in Chinese MS patients. Hence, we pertbrmed a MassArray Assay to genotype the previously reported variants located in the transcription regulation genes in order to elucidate their role in the Chinese MS patients. Methods： One hundred and forty-two relapsing-remitting MS （RRMS） patients and 301 healthy controls were consecutively collected from September 2, 2008, to June 7, 2013, as stage 1 subjects. Eight reported transcription regulation-related single-nucleotide polymorphisms （SNPs） were genotyped using the Sequenom MassArray system. In stage 2, another 44 RRMS patients and 200 healthy controls were consecutively collected and Sanger sequenced from April 7, 2015, to June 29, 2017, for the validation of positive results in stage 1. Differences in allele and genotype frequencies between patients and healthy controls, odds ratios, and 95% confidence intervals were calculated with the Chi-square test or Fisher＇s exact test. Hardy-Weinberg equilibrium was tested also using the Chi-square test. Results： In stage 1 analysis, we confirmed only one previously reported risk variant, rsl 1129295 in EOMES gene. We found that the frequency ofT/T genotype was much higher in MS group （χ2 = 10.251, P = 0.005） and the T allele ofrsl 1129295 increased the risk of MS （χ2 = 10.022, P = 0.002）. In stage 2 and combined analyses, the T allele of rsl 1129295 still increased the risk of MS （χ2 = 4.586, P- 0.030 and×2 = 16.378, P = 5.19×10 ^-5, respectively）. Conclusions： This study enhances the knowledge that the variant of EOMES is associated with increasing risk in Chinese RRMS patients and provides a potential therapeutic target in RRMS.展开更多
文摘Interaction detection in large-scale genetic asso- ciation studies has attracted intensive research interest, since many diseases have complex traits. Various approaches have been developed for finding significant genetic interactions. In this article, we propose a novel framework SRMiner to detect interacting susceptible and protective genotype patterns. SR- Miner can discover not only probable combination of single nucleotide polymorphisms （SNPs） causing diseases but also the corresponding SNPs suppressing their pathogenic func- tions, which provides a better prospective to uncover the un- derlying relevance between genetic variants and complex dis- eases. We have performed extensive experiments on several real WeUcome Trust Case Control Consortium （WTCCC） datasets. We use the pathway-based and the protein-protein interaction （PPI） network-based evaluation methods to verify the discovered patterns. The results show that SRMiner successfully identifies many disease-related genes verified by the existing work. Furthermore, SRMiner can also infer some uncomfirmed but highly possible disease-related genes.
基金This work was supported by the Major State Basic Research Development program of Chinathe National High Technology Research and Development Program of China.
文摘In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values with a large numberof samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data,we developed a robust and user-friendly software platform with a series of tools for analysis in association study withhigh efficiency. The platform has been well evaluated by several sets of real data.
基金supported by grants from the National Natural Science Foundation of China[No.81872641]Natural Science Foundation of Hunan Province[No.2023JJ40357].
文摘Objective To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease(NAFLD).Methods Literature from Web of Science,PubMed,and Embase between January 1980 and September 2022 was systematically searched.Meta-analyses of the genetic variants were conducted using at least five data sources.The epidemiologic credibility of the significant associations was graded using the Venice criteria.Results Based on literature screening,399 eligible studies were included,comprising 381 candidate gene association,16 genome-wide association,and 2 whole-exome sequencing studies.We identified 465 genetic variants in 173 genes in candidate gene association studies,and 25 genetic variants in 17 genes were included in the meta-analysis.The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD,with cumulative epidemiological evidence of an association graded as strong for two variants in two genes(HFE,TNF),moderate for four variants in three genes(TM6SF2,GCKR,and ADIPOQ),and weak for five variants in five genes(MBOAT7,PEMT,PNPLA3,LEPR,and MTHFR).Conclusion This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD,which may help understand the genetic architecture of NAFLD risk.
基金Supported by A Damon Runyon Cancer Research Foundation Clinical Investigator Award,CI-8An R25 training grant from the National Cancer Institute,R25T CA094186+1 种基金The Case Center for Transdisciplinary Research on Energetics and Cancer,1U54 CA-116867-01A National Cancer Institute K22 Award,1K22 CA120545-01
文摘AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.
基金funded by the National Natural Science Foundation of China(41390240 and 41571130010)the 111 Project(B14001)
文摘For lifetime non-smokers, lung cancer risk is mainly associated with inhalation exposure to air pollution. For the Chinese population, indoor air pollution due to solid fuel combustion has been the primary source of inhalation exposure for decades. Polycyclic aromatic hydrocarbons （PAHs） are the by-products of incomplete combustion.
文摘Backgrounds: Although many disease-associated common variants have been discovered through genome-wide association studies, much of the genetic effects of complex diseases have not been explained. Population-based association studies are vulnerable to population stratification. A possible solution is to use family-based tests. However, if tests only estimate the genetic effect from the within-family variation to avoid population stratification, they may ignore the useful genetic information from between-family variation and lose power. Methods: We have developed an adaptive weighted sum test for family-based association studies. The new test uses data driven weights to combine two test statistics, and the weights measure the strength of population stratification. When population stratification is strong, the proposed test will automatically put more weight on one statistic derived from within-family variation to maintain robustness against spurious positives. On the other hand, when the effect of population stratification is relatively weak, the proposed test will automatically put more weight on the other statistic derived from both within-family and between-family variation to make use of both sources of genetic variation;and at the same time, the degrees of freedom of the test will be reduced and power of the test will be increased. Results: In our study, the proposed method achieves a higher power in most scenarios of linkage disequilibrium structure as well as Hap Map data from different genes under different population structures while still keeping its robustness against population stratification.
基金supported by the National Institutes of Health,USA (MH101054)
文摘Schizophrenia（SCZ） is a complex and heterogeneous mental disorder that affects about 1% of global population. In recent years,considerable progress has been made in genetic studies of SCZ. A number of common variants with small effects and rare variants with relatively larger effects have been identifi ed. These variants include risk loci identifi ed by genome-wide association studies,rare copy-number variants identifi ed by comparative genomic analyses,and de novo mutations identified by high-throughput DNA sequencing. Collectively,they contribute to the heterogeneity of the disease. In this review,we update recent discoveries in the fi eld of SCZ genetics,and outline the perspectives of future directions.
基金supported by the Research Project of Central Health Care Special Fund,China,No.W2017BJ52(to JZ)
文摘Early-and late-onset narcolepsy constitutes two distinct diagnostic subgroups.However,it is not clear whether symptomology and genetic risk factors differ between early-and late-onset narcoleptics.This study compared clinical data and single-nucleotide polymorphisms(SNPs)between early-and late-onset patients in a large cohort of 899 Han Chinese narcolepsy patients.Blood,cerebrospinal fluid,and clinical data were prospectively collected from patients,and patients were genotyped for 40 previously reported narcolepsy risk-conferring SNPs.Genetic risk scores(GRSs),associations of five different sets of SNPs(GRS1–GRS5)with early-and late-onset narcolepsy,were evaluated using logistic regression and receiver operating characteristic curves.Mean sleep latency was significantly shorter in early-onset cases than in late-onset cases.Symptom severity was greater among late-onset patients,with higher rates of sleep paralysis,hypnagogic hallucinations,health-related quality of life impairment,and concurrent presentation with four or more symptoms.Hypocretin levels did not differ significantly between early-and late-onset cases.Only rs3181077(CCR1/CCR3)and rs9274477(HLA-DQB1)were more prevalent among early-onset cases.Only GRS1(26 SNPs;OR=1.513,95%CI:0.893–2.585;P<0.05)and GRS5(6 SNPs;OR=1.893,95%CI:1.204–2.993;P<0.05)were associated with early-onset narcolepsy,with areas under the receiver operating characteristic curves of 0.731 and 0.732,respectively.Neither GRS1 nor GRS5 included SNPs in HLA regions.Our results indicate that symptomology and genetic risk factors differ between early-and late-onset narcolepsy.This protocol was approved by the Institutional Review Board(IRB)Panels on Medical Human Subjects at Peking University People’s Hospital,China(approval No.Yuanlunshenlinyi 86)in October 2011.
文摘The disease burden of diabetic retinopathy(DR)is tremendous around the world.While DR is correlated with hemoglobin A1c(HbA1c)and duration of diabetes,genetic differences likely account for variation in susceptibility to DR.DR is a polygenic disorder with demonstrated heritability.However,linkage and admixture analyses,candidate gene association studies,and genome-wide association studies(GWAS)have not identified many loci for DR that can be consistently replicated.Larger,collaborative,multi-ethnic GWAS are needed to identify common variants with small effects.Rigorous defining of controls groups as patients with a long duration of diabetes without DR,and case groups as patients with severe DR will also aid in finding genes associated with DR.Replication in independent cohorts will be key to establishing associated loci for DR.Investigations of mitochondrial DNA and epigenetics in DR are ongoing.Whole exome sequencing presents new opportunities to identify rare variants that might be implicated in DR development.Continued research in the genetic epidemiology of DR is needed,with the potential to elucidate pathogenesis and treatment of an important disease.
基金supported by the Programme Blanc de l’Agence National de la Recherche.
文摘Family-based tests of association between a genetic marker and a disease constitute a common design to dissect the genetic architecture of complex traits. The FBAT software is one of the most popular tools to perform such studies. However, researchers are also often interested in the genetic contribution to a more specific manifestation of the phenotype (e.g. severe vs. non-severe form) known as a secondary outcome. Here, what we demonstrate is the limited power of the classical formulation of the FBAT statistic to detect the effect of genetic variants that influence a secondary outcome, in particular when these variants also impact on the onset of the disease, the primary outcome. We prove that this loss of power is driven by an implicit hypothesis, and we propose a derivation of the original FBAT statistic, free from this implicit hypothesis. Finally, we demonstrate analytically that our new statistic is robust and more powerful than FBAT for the detection of association between a genetic variant and a secondary outcome.
文摘Transmission disequilibrium tests (TDT) is a well-known case-parents family-based method to detect the association between genetic polymorphisms and a disease phenotype. Various extensions of the TDT have been developed and widely applied in medical research. In this article, we introduced a simple simulation algorithm based on a transition model to generate general nuclear families rather than trios to simulate multiple tightly linked markers. The simulations show that the empirical distributions of the test statistics coincide with the expected distribution under the null hypothesis.
文摘Recently,new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis.The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease.All these new genes apply to each of the four hits.Additionally,new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis.The IgA treatment is also changed included the future possibilities.The treatment of the chronic kidney disease,associated with the nephropathy,is mandatory,since the beginning of the disease.The classical immunosuppressive agents have poor effect.The corticosteroids remain an important cornerstone in any phase of the disease.More effect is related to the treatment of B cells and plasma cells.In particular,in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents.Most of these studies are to date in phase II/III.Finally,new agents targeting complement are arising.These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.
文摘<strong>Introduction:</strong> The goal of this study was to utilize physical characteristics instead of placing subjects in arbitrary diagnostic categories to test for associations with genetic variants. <strong>Methods:</strong> Forty-four single nucleotide polymorphisms were tested for association with specific cephalometric measurements in thirty-nine University of Pittsburgh Dental Registry and DNA Repository orthodontic subjects. Cephalometric measurements included an evaluation of FMA, a Wits appraisal, and a Steiner’s ANB analysis. Genetic markers were genotyped using polymerase chain reaction and Taqman chemistry. Chi-square and Fischer’s exact tests (α = 0.05) were used in investigation of overrepresentation of marker alleles. Samples were divided into groups based upon having an FMA, Wits, or ANB measurement above or below the mean of the cohort studied. Secondary analysis was done for sex and ethnicity to determine their effect on FMA, Wits, or ANB. <strong>Results: </strong>An association between FMA measurements was discovered in the following genes: ACTN3, CASP4, ESR1, FGF13, KRT7, and PITX2. An association between Wits measurements was discovered in the following genes: ACTN2, BTBD11, CASP4, FGF3, and FGF10. No associations were found with ANB.<strong> Conclusions: </strong>Genetic markers in several genes at different loci may contribute to craniofacial deformities in humans. This approach of using physical measurements may be an advantage to placing patients in arbitrary diagnostic categories.
基金This study was supported by grants from the National Natural Science Foundation of China （No.81060239 and No.30872132）.
文摘Background Genetic association studies on populations of European origin have identified the DCDC2 gene as a susceptibility locus for developmental dyslexia.Here,we sought to investigate the association of DCDC2 polymorphisms with developmental dyslexia in children of Han Chinese origin.Methods We undertook a case-control genetic association study on 76 dyslexic children and 79 non-dyslexic matched controls.We isolated DNA from oral mucosal cell samples and genotyped two DCDC2 coding-sequence single nucleotide polymorphisms,rs2274305 and rs6456593,in each sample using SNaPshot single nucleotide extension.We compared the allele and genotype frequencies between the groups using the X2 test and analyzed the relationship between dyslexia and the polymorphism at both loci using unconditional logistic regression.We also predicted haplotypes and compared their frequencies between the two groups.Results The differences in the genotype distribution and the allelic genes of the two single nucleotide luci of the DCDC2 gene,rs2274305 and rs6456593,between the two dyslexic and non-dyslexic groups were statistically meaningless （P 〉0.05）.The differences in the haplotype distributions of the DCDC2 gene between the dyslexic and normal group were statistically meaningless （P 〉0.05）.Conclusion The DCDC2 gene may not be a susceptibility factor for developmental dyslexia among the Han Chinese.However,methodological issues may have prevented the detection of oositive associations.
基金This work was supported by a grant from the National Natural Science Foundation of China （No.30771833）.
文摘Background Parkinson＇s disease （PD） is an autosomally inherited neurodegenerative disease in elderly people.The etiology of PD has long been thought to be associated with both genetic and environmental factors.To explore potential genetic risk factors for PD in the northern Han Chinese population,we investigated three single nucleotide polymorphisms （SNPs） （rs4538475,rs11107 and rs12564040） in the BST1,PARK15 and PARK9 genes.Methods Genomic DNA from 215 PD patients and 212 matched controls was amplified in two independent PCR systems and subsequently genotyped by digestion with the endonuclease Pstl.Genetic parameter and association studies were carried out with SPSS 13.0 and PLINK 1.07 software.Results We could accurately detect all genotypes in the three loci with the PCR-RFLP or mismatched PCR-RFLP techniques.The observed heterozygosities of the rs4538475 and rs11107 loci in PD and control groups ranged from 0.460-0.481 and 0.410-0.441,in BST1,PARK15 respectively,while we detected no heterozygosity at the rs12564040 locus in PARK9.The similar distributions of genotypic frequency between both groups suggest that the three SNPs investigated in this study are unlikely to play roles as common risk factors or pathogenic mutations for PD in northern Han Chinese.Conclusion The SNPs investigated in the BST1,PARK15 and PARK9 genes associated with PD susceptibility are not associated with PD in the northern Han Chinese population.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 30850006） and Foundation ol People＇s Hospital of Xinjiang Uygur Autonomous Region （No. 20080106）.
文摘Background Coordinated regulation of nutrient and inflammatory responses by six transmembrane epithelial antigen of prostate 4 （STEAP4） was essential for metabolic homeostasis. STEAP4 expression in human white adipose tissuewas associated with obesity. This study aimed to evaluate association between STEAP4 genetic polymorphisms and obesity in Uygur Chinese general population.Methods The functional regions of STEAP4 gene were sequenced in 96 Uygur with obesity （body mass index （BMI）〉30 kg/m2）. Representative variations were selected according to the function and linkage disequilibrium and genotyped in 1507 obesity （BMI ≥25 kg/m2） and 825 non-obesity control （BMI ＜25 kg/m2）, all of whom were selected from epidemiology study of obesity-related diseases during January to February 2007 among Uygur population in Hetian area of Xinjiang Uygur Autonomous Region.Results Fourteen novel and 6 known single nucleotide polymorphism （SNPs）, including 2 nonsynonymous SNPs （nsSNPs）, in the STEAP4 gene were identified. Of the 3 representative SNPs, the nsSNP rs1981529 （Gly75Asp, 224A/G）was significantly associated with obesity phenotype （additive P/Pc=0.001/0.006, dominant P/Pc=0.003/0.018, odds ratio （OR） and 95％ confidence interval （CI） adjusted for age, gender and drinking 0.755 （0.641-0.890） and 0.750（0.621-0.907）, respectively）. By the multiple linear regression analysis, the quantitative phenotypes of BMI （P/Pc=0.002/0.004） and waist circumference （P/Pc=0.004/0.008） were found to be significantly associated with the genotypes of rs1981529 （Gly75Asp, 224A/G） in Uygur general population, and effect size （beta value） of one allele G of rs1981529 （Gly75Asp, 224A/G） was-0.553 kg/m2 for BMI and -1.311 cm for waist circumference after controlling age,gender and drinking factors.Conclusions The present study shows an association of the common variation rs1981529 （Gly75Asp, 224A/G） in the STEAP4 gene with obesity in Uygur general population. Further studies should replicate the results using larger populations.
基金This study was supported by the grants from the National Natural Science Foundation of China （No. 81371414 and No. 81125009）.
文摘Background： Multiple sclerosis （MS） is a common central nervous system autoimmune disorder. Increasing number of genome-wide association study （GWAS） analyses hint that MS is strongly associated with genetics. Unfortunately, almost all the GWAS analyses were Caucasian population based. Numbers of risk loci might not be replicated in Chinese MS patients. Hence, we pertbrmed a MassArray Assay to genotype the previously reported variants located in the transcription regulation genes in order to elucidate their role in the Chinese MS patients. Methods： One hundred and forty-two relapsing-remitting MS （RRMS） patients and 301 healthy controls were consecutively collected from September 2, 2008, to June 7, 2013, as stage 1 subjects. Eight reported transcription regulation-related single-nucleotide polymorphisms （SNPs） were genotyped using the Sequenom MassArray system. In stage 2, another 44 RRMS patients and 200 healthy controls were consecutively collected and Sanger sequenced from April 7, 2015, to June 29, 2017, for the validation of positive results in stage 1. Differences in allele and genotype frequencies between patients and healthy controls, odds ratios, and 95% confidence intervals were calculated with the Chi-square test or Fisher＇s exact test. Hardy-Weinberg equilibrium was tested also using the Chi-square test. Results： In stage 1 analysis, we confirmed only one previously reported risk variant, rsl 1129295 in EOMES gene. We found that the frequency ofT/T genotype was much higher in MS group （χ2 = 10.251, P = 0.005） and the T allele ofrsl 1129295 increased the risk of MS （χ2 = 10.022, P = 0.002）. In stage 2 and combined analyses, the T allele of rsl 1129295 still increased the risk of MS （χ2 = 4.586, P- 0.030 and×2 = 16.378, P = 5.19×10 ^-5, respectively）. Conclusions： This study enhances the knowledge that the variant of EOMES is associated with increasing risk in Chinese RRMS patients and provides a potential therapeutic target in RRMS.
