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1.
全基因组关联研究(genome-wide association study, GWAS)自2005年首次发表以来已不断增进人们对疾病遗传机制的认识,结合系统生物学并改进统计分析方法是对GWAS数据进行深度挖掘的重要途径。通路分析(pathway analysis)将GWAS所检测的遗传变异根据一定的生物学含义组合为集合进行分析,有利于发现对疾病单独效应小却在通路中相互关联的遗传变异,更有利于进行生物学解释。当前通路分析在GWAS数据上已有较为广泛的应用并取得初步成果。与此同时,通路分析的统计方法仍在不断发展。本文旨在介绍现有直接以SNP为对象的GWAS通路分析算法,根据方法中是否采用核函数分为非核算法和核算法两大类,其中非核算法主要包括基因功能富集分析(gene set enrichment analysis, GSEA)和分层贝叶斯优取(hierarchical Bayes prioritization, HBP),核算法包括线性核(linear kernel, LIN)、状态认证核(identity-by-status kernel, IBS)和尺度不变核(powered exponential kernel)。通过介绍这些方法的计算原理和优缺点,以期为新算法的构建提供更好的思路,为GWAS领域研究方法的选择提供参考。 相似文献
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L. A. V. Magno D. M. Miranda F. S. Neves G. J. Pimenta M. P. Mello L. A. De Marco H. Correa M. A. Romano‐Silva 《Genes, Brain & Behavior》2010,9(4):411-418
We tested the hypothesis that the presence of AKT1 and AKTIP polymorphisms, target genes that encode key proteins in the signaling of dopaminergic and serotonergic systems, is associated with suicidal behavior in bipolar patients. The subjects were 273 patients diagnosed with bipolar disorder I or II (age = 41.4 ± 12.9). TaqMan single‐nucleotide polymorphism genotyping assays (AKT1: rs2494731, rs3803304, rs3730358, rs10149779, rs2494746, rs1130214 and rs249878; AKTIP: rs9302648 and rs7189819) were used. We found that the AKT1 marker showed an association with suicide attempts (rs1130214, P < 0.05) and attempted violent attacks (rs2494746, P < 0.05). One out of the seven tested markers of AKT1 attained significant genotype association with violent attempt (rs2494731; P < 0.05). A significant association was detected in the AKT1 haplotype test. We did not observe an association between suicidal behavior and AKTIP variants and also did not find an interaction between AKTIP and AKT1 polymorphisms. In addition, we found that demographic and clinical data are associated with lifetime history of suicide attempts. Our data suggest that demographic and clinical characteristics and AKT1 single markers and haplotypes, but not AKTIP polymorphisms or interactions between AKT1 and AKTIP, are associated with increased risk for suicidal behavior in bipolar patients. 相似文献
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S.-Y. Liao S.-H. Lin C.-M. Liu M. H. Hsieh T. J. Hwang S. K. Liu S.-C. Guo H.-G. Hwu and W. J. Chen 《Genes, Brain & Behavior》2009,8(2):228-237
This study examined the relations of genetic variants in catechol- O -methyltransferase ( COMT ) gene, including rs737865 in intron 1, rs4680 in exon 4 (Val158Met) and downstream rs165599, to schizophrenia and its related neurocognitive functions in families of patients with schizophrenia. Totally, 680 individuals from 166 simplex (166 affected members and 354 nonpsychotic first-degree relatives) and 46 multiplex families (85 affected members and 75 nonpsychotic first-degree relatives) were interviewed using Diagnostic Interview for Genetic Studies, administered Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT), and drawn for venous blood. Both categorical (dichotomizing families on affected members' neurocognitive performance) and quantitative approaches toward the WCST and CPT performance scores were employed using the family-based association test and the variance components framework, respectively. Both false discovery rate and permutations were used to adjust for multiple testing. The genotypes of rs4680 were associated with both the WCST and CPT performance scores in these families, but not with schizophrenia per se in either whole sample or subgroup analyses. Meanwhile, the other two single nucleotide polymorphisms were differentially associated with the two tasks. For WCST indexes, regardless of subgroup analyses or quantitative approach, only rs737865 exhibited moderate associations. For CPT indexes, rs737865 exhibited association for the subgroup with deficit on CPT reaction time, whereas rs165599 exhibited association for the subgroup with deficit on CPT d' as well as quantitative undegraded d'. Our results indicate that the genetic variants in COMT might be involved in modulation of neurocognitive functions and hence conferring increased risk to schizophrenia. 相似文献
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The software tool PBEAM provides a parallel implementation of the BEAM, which is the first algorithm for large scale
epistatic interaction mapping, including genome-wide studies with hundreds of thousands of markers. BEAM describes
markers and their interactions with a Bayesian partitioning model and computes the posterior probability of each marker sets
via Markov Chain Monte Carlo (MCMC). PBEAM takes the advantage of simulating multiple Markov chains
simultaneously. This design can efficiently reduce ~n-fold execution time in the circumstance of n CPUs. The
implementation of PBEAM is based on MPI libraries.
Availability
PBEAM is available for download at http://bioinfo.au.tsinghua.edu.cn/pbeam/ 相似文献5.
A. Hishimoto M. Fukutake K. Mouri Y. Nagasaki M. Asano Y. Ueno N. Nishiguchi O. Shirakawa 《Genes, Brain & Behavior》2010,9(5):498-502
Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop suicidal behavior. Genetic factors for suicidal behavior have been observed in family, twin, and adoption studies. Because alcohol dehydrogenase (ADH1B) His47Arg and mitochondrial aldehyde dehydrogenase (ALDH2) Glu487Lys single nucleotide polymorphisms (SNPs), which affect alcohol metabolism, have been reported to exert significant impacts on alcohol consumption and on the risk for alcoholism in East Asia populations, we explored associations of the two functional SNPs with suicide using a case–control study of 283 completed suicides and 319 control subjects in the Japanese population. We found that the inactive ALDH2 allele (487Lys) was significantly less frequent in the completed suicides (19.3%) than in the controls (29.3%), especially in males, whereas this was not the case in females. The males bearing alcoholism‐susceptible homozygotes at both loci (inactive ADH1B Arg/Arg and active ALDH2 Glu/Glu genotypes) have a 10 times greater risk for suicide compared with the males bearing alcoholism‐protective homozygotes at both loci. Our data show the genetic impact of the two polymorphisms on suicidal behavior in the Japanese population, especially in males. Because we did not verify the daily alcohol consumption, the association of these SNPs with suicide might be due to alcoholism itself. Further studies using case–control subjects, which verifies the details of current and past alcohol consumption and diagnosis for alcoholism, are required to confirm these findings. 相似文献
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5个精神分裂症高发家系与COMT关联的分析 总被引：6，自引：1，他引：6
本研究旨在探测儿茶酚氧位甲基转移酶基因（COMT）多态性与精神分裂症（SP）的关系,搜寻中国汉族人精神分裂症易患性基因。 应用聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）方法对5个精神分裂症高发家系进行初步研究。 用改进的传递/不平衡（TDT）进行统计分析,结果表明,在5个精神分裂症高发家系中,COMT基因与精神分裂症相关联（P=0.0455）。 研究结果提示,在我们研究的家系中,22号染色体长臂（22q11.2）可能存在精神分裂症易患性基因。Abstract:This study is to explore the relationship between polymorphism of Catechol O-methyltransferase gene and schizophrenia.Search for a gene predisposing to schizophrenia in the Han nationality in China.Five pedigrees with high incidence of schizophrenia were studied by polymerize chain reaction(PCR) and restriction fragment length polymorphism(RFLP) technique.Statistics analysis of the transmission/disequilibrium test (TDT) showed that the COMT gene is associatted with schizophrenia in the five pedigree with high incidence schizophrenia(P=0.0455).The results suggest that there might have a schizophrenia liability gene on 22 chromosome (22q11.2) in our studied pedigrees. 相似文献
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Probability of detecting disease-associated single nucleotide polymorphisms in case-control genome-wide association studies 总被引：1，自引：0，他引：1
Some case-control genome-wide association studies (CCGWASs) select promising single nucleotide polymorphisms (SNPs) by ranking corresponding p-values, rather than by applying the same p-value threshold to each SNP. For such a study, we define the detection probability (DP) for a specific disease-associated SNP as the probability that the SNP will be "T-selected," namely have one of the top T largest chi-square values (or smallest p-values) for trend tests of association. The corresponding proportion positive (PP) is the fraction of selected SNPs that are true disease-associated SNPs. We study DP and PP analytically and via simulations, both for fixed and for random effects models of genetic risk, that allow for heterogeneity in genetic risk. DP increases with genetic effect size and case-control sample size and decreases with the number of nondisease-associated SNPs, mainly through the ratio of T to N, the total number of SNPs. We show that DP increases very slowly with T, and the increment in DP per unit increase in T declines rapidly with T. DP is also diminished if the number of true disease SNPs exceeds T. For a genetic odds ratio per minor disease allele of 1.2 or less, even a CCGWAS with 1000 cases and 1000 controls requires T to be impractically large to achieve an acceptable DP, leading to PP values so low as to make the study futile and misleading. We further calculate the sample size of the initial CCGWAS that is required to minimize the total cost of a research program that also includes follow-up studies to examine the T-selected SNPs. A large initial CCGWAS is desirable if genetic effects are small or if the cost of a follow-up study is large. 相似文献
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Xianyong Yin Debraj Bose Annie Kwon Sarah C. Hanks Anne U. Jackson Heather M. Stringham Ryan Welch Anniina Oravilahti Lilian Fernandes Silva FinnGen Adam E. Locke Christian Fuchsberger Susan K. Service Michael R. Erdos Lori L. Bonnycastle Johanna Kuusisto Nathan O. Stitziel Ira M. Hall Jean Morrison Samuli Ripatti Aarno Palotie Nelson B. Freimer Francis S. Collins Karen L. Mohlke Laura J. Scott Eric B. Fauman Charles Burant Michael Boehnke Markku Laakso Xiaoquan Wen 《American journal of human genetics》2022,109(10):1727-1741
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Brunilda Balliu Jeanine J. Houwing‐Duistermaat Stefan Bhringer 《Biometrical journal. Biometrische Zeitschrift》2019,61(3):747-768
Marginal tests based on individual SNPs are routinely used in genetic association studies. Studies have shown that haplotype‐based methods may provide more power in disease mapping than methods based on single markers when, for example, multiple disease‐susceptibility variants occur within the same gene. A limitation of haplotype‐based methods is that the number of parameters increases exponentially with the number of SNPs, inducing a commensurate increase in the degrees of freedom and weakening the power to detect associations. To address this limitation, we introduce a hierarchical linkage disequilibrium model for disease mapping, based on a reparametrization of the multinomial haplotype distribution, where every parameter corresponds to the cumulant of each possible subset of a set of loci. This hierarchy present in the parameters enables us to employ flexible testing strategies over a range of parameter sets: from standard single SNP analyses through the full haplotype distribution tests, reducing degrees of freedom and increasing the power to detect associations. We show via extensive simulations that our approach maintains the type I error at nominal level and has increased power under many realistic scenarios, as compared to single SNP and standard haplotype‐based studies. To evaluate the performance of our proposed methodology in real data, we analyze genome‐wide data from the Wellcome Trust Case‐Control Consortium. 相似文献
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Govert den Hartogh 《Bioethics》2016,30(9):672-680
In suicidology, the common view is that ‘rational’ suicides occur only rarely, because the competence of people who want to end their lives is compromised by mental illness. In the Netherlands and Flanders, however, patients’ requests for euthanasia or assistance in suicide are granted in 5300 and 1400 cases a year respectively, and in all these cases at least two doctors have confirmed the patient's competence. The combination of these two findings is puzzling. In other countries one would expect at least some of these people to end their own lives. The article argues that we can distinguish between two types of suicide with clustering characteristics. In cases of the first type, the agent doesn't carefully plan his action, doesn't communicate his plans to relatives or others, and uses violent means. In such cases it is reasonable to presume lack of competence. The other type has the opposite characteristics. The most plausible explanation of our problem is that suicides of the second kind are invisible to suicidology, because they tend not to be registered as suicides at all. 相似文献
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人类身高的遗传学研究进展 总被引：1，自引：0，他引：1
人类身高是由环境和遗传因素共同决定的,遗传学研究发现遗传因素对身高差异的影响更大。身高是典型的多基因遗传性状,科研人员试图运用传统的连锁分析和关联分析寻找和发现对人类身高具有显著影响的常见DNA序列变异,但进展缓慢。近年来,随着基因分型和DNA测序技术的发展,人类身高的遗传学研究取得了很多突破性进展。全基因组关联分析(GWAS)的应用,发现和证实了上百个与人类身高相关的单核苷酸多态性位点(SNPs),拓展了人们对人类生长和发育的相关遗传学认识,同时也为研究人类其他复杂性状提供了理论依据和借鉴。本文综述了人类身高的遗传学研究进展,探讨了目前该研究领域所存在的问题和未来发展方向,以期为今后人类身高相关的遗传学研究提供参考和借鉴。 相似文献
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“发酵工程”教学的研究与思考 总被引：2，自引：0，他引：2
发酵工程是食品工程、生物工程、生物技术等专业的重要专业课,课程内容丰富、涉及面宽。针对该课程的特点,从教材建设、课程内容、考核方式、教学方法等方面思考与探索该课程教学思路,取得了良好效果。 相似文献
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Xuemin Cao Yuzhe Wang Dingming Shu Hao Qu Chenglong Luo Xiaoxiang Hu 《Animal genetics》2020,51(5):741-751
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Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men. Ge nome-wide association st udies (GWAS) has been highly successful in discovering susceptibility loci for prostate cancer. Currently, more than twenty GWAS have identified more than fifty common variants associated with susceptibility with PCa. Yet with the increase in loci, voices from the scientific society are calling for more. In this review, we summarize current findings, discuss the common problems troubling current studies and shed light upon possible breakthroughs in the future. GWAS is the beginning of something wonderful. Although we are quite near the end of the beginning, post-GWAS studies are just taking off and future studies are needed extensively. It is believed that in the future GWAS information will be helpful to build a comprehensive system intergraded with PCa prevention, diagnosis, molecular classification, personalized therapy. 相似文献
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Summary Population admixture can be a confounding factor in genetic association studies. Family‐based methods ( Rabinowitz and Larid, 2000 , Human Heredity 50, 211–223) have been proposed in both testing and estimation settings to adjust for this confounding, especially in case‐only association studies. The family‐based methods rely on conditioning on the observed parental genotypes or on the minimal sufficient statistic for the genetic model under the null hypothesis. In some cases, these methods do not capture all the available information due to the conditioning strategy being too stringent. General efficient methods to adjust for population admixture that use all the available information have been proposed ( Rabinowitz, 2002 , Journal of the American Statistical Association 92, 742–758). However these approaches may not be easy to implement in some situations. A previously developed easy‐to‐compute approach adjusts for admixture by adding supplemental covariates to linear models ( Yang et al., 2000 , Human Heredity 50, 227–233). Here is shown that this augmenting linear model with appropriate covariates strategy can be combined with the general efficient methods in Rabinowitz (2002) to provide computationally tractable and locally efficient adjustment. After deriving the optimal covariates, the adjusted analysis can be carried out using standard statistical software packages such as SAS or R . The proposed methods enjoy a local efficiency in a neighborhood of the true model. The simulation studies show that nontrivial efficiency gains can be obtained by using information not accessible to the methods that rely on conditioning on the minimal sufficient statistics. The approaches are illustrated through an analysis of the influence of apolipoprotein E (APOE) genotype on plasma low‐density lipoprotein (LDL) concentration in children. 相似文献
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Emily E. Hartwell Alison K. Merikangas Shefali S. Verma Marylyn D. Ritchie Henry R. Kranzler Rachel L. Kember 《Addiction biology》2022,27(1):e13099
Polygenic risk scores (PRS) represent an individual's summed genetic risk for a trait and can serve as biomarkers for disease. Less is known about the utility of PRS as a means to quantify genetic risk for substance use disorders (SUDs) than for many other traits. Nonetheless, the growth of large, electronic health record-based biobanks makes it possible to evaluate the association of SUD PRS with other traits. We calculated PRS for smoking initiation, alcohol use disorder (AUD), and opioid use disorder (OUD) using summary statistics from the Million Veteran Program sample. We then tested the association of each PRS with its primary phenotype in the Penn Medicine BioBank (PMBB) using all available genotyped participants of African or European ancestry (AFR and EUR, respectively) (N = 18,612). Finally, we conducted phenome-wide association analyses (PheWAS) separately by ancestry and sex to test for associations across disease categories. Tobacco use disorder was the most common SUD in the PMBB, followed by AUD and OUD, consistent with the population prevalence of these disorders. All PRS were associated with their primary phenotype in both ancestry groups. PheWAS results yielded cross-trait associations across multiple domains, including psychiatric disorders and medical conditions. SUD PRS were associated with their primary phenotypes; however, they are not yet predictive enough to be useful diagnostically. The cross-trait associations of the SUD PRS are indicative of a broader genetic liability. Future work should extend findings to additional population groups and for other substances of abuse. 相似文献
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Mathew Littlejohn Talia Grala Kathryn Sanders Caroline Walker Garry Waghorn Kevin Macdonald Richard Spelman Steve Davis Russell Snell 《Animal genetics》2012,43(6):781-784
Animal growth relative to food energy input is of key importance to agricultural production. Several recent studies highlighted genetic markers associated with food conversion efficiency in beef cattle, and there is now a requirement to validate these associations in additional populations and to assess their potential utility for selecting animals with enhanced food‐use efficiency. The current analysis tested a population of dairy cattle using 138 DNA markers previously associated with food intake and growth in a whole‐genome association analysis of beef animals. Although seven markers showed point‐wise significance at P < 0.05, none of the single‐nucleotide polymorphisms tested were significantly associated with food conversion efficiency after correction for multiple testing. These data do not support the involvement of this subset of previously implicated markers in the food conversion efficiency of the physiologically distinct New Zealand Holstein‐Friesian dairy breed. 相似文献
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