PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses
TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Abstract: Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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Elizabeth K. Speliotes1, Elizabeth K. Speliotes2, Cristen J. Willer3, Sonja I. Berndt +410 more•Institutions (86)
TL;DR: Genetic loci associated with body mass index map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor, which may provide new insights into human body weight regulation.
Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
2,632 citations
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Wellcome Trust Centre for Human Genetics1, University of Liège2, University of Chicago3, Yale University4, University of Pittsburgh5, Montreal Heart Institute6, Massachusetts Institute of Technology7, Johns Hopkins University8, University of Toronto9, Cedars-Sinai Medical Center10, McGill University11, Harvard University12, Ghent University Hospital13, Katholieke Universiteit Leuven14, Free University of Brussels15, Paris Diderot University16, Western General Hospital17, King's College London18, University of Oxford19, Wellcome Trust Sanger Institute20, University of Cambridge21, Newcastle University22
TL;DR: The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1, which offer promise for informed therapeutic development.
Abstract: Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.
2,584 citations
Cites methods from "PLINK: A Tool Set for Whole-Genome ..."
...Interaction tests were done using the case-only epistasis test implemented in PLIN...
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Stephen Sawcer1, Garrett Hellenthal2, Matti Pirinen2, Chris C. A. Spencer2 +262 more•Institutions (67)
TL;DR: In this article, a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, they have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
2,511 citations
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TL;DR: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs), which were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders.
Abstract: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section.
2,361 citations
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TL;DR: New tools implemented in the adegenet 1.3-1 package for handling and analyzing genome-wide single nucleotide polymorphism (SNP) data are introduced, using a bit-level coding scheme for SNP data and parallelized computation.
Abstract: Summary: While the R software is becoming a standard for the analysis of genetic data, classical population genetics tools are being challenged by the increasing availability of genomic sequences. Dedicated tools are needed for harnessing the large amount of information generated by next-generation sequencing technologies. We introduce new tools implemented in the adegenet 1.3-1 package for handling and analyzing genome-wide single nucleotide polymorphism (SNP) data. Using a bit-level coding scheme for SNP data and parallelized computation, adegenet enables the analysis of large genome-wide SNPs datasets using standard personal computers.
Availability:adegenet 1.3-1 is available from CRAN: http://cran.r-project.org/web/packages/adegenet/. Information and support including a dedicated forum of discussion can be found on the adegenet website: http://adegenet.r-forge.r-project.org/. adegenet is released with a manual and four tutorials totalling over 300 pages of documentation, and distributed under the GNU General Public Licence (≥2).
Contact: t.jombart@imperial.ac.uk
Supplementary Information:Supplementary data are available at Bioinformatics online.
2,288 citations
References
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TL;DR: In this paper, a different approach to problems of multiple significance testing is presented, which calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate, which is equivalent to the FWER when all hypotheses are true but is smaller otherwise.
Abstract: SUMMARY The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.
83,420 citations
"PLINK: A Tool Set for Whole-Genome ..." refers methods in this paper
...org The American Journal of Human Genetics Volume 81 September 2007 565 multiple-test corrections are also available, including those based on Bonferroni correction and false-discovery rate.(31) IBD estimation....
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TL;DR: Pritch et al. as discussed by the authors proposed a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations, which can be applied to most of the commonly used genetic markers, provided that they are not closely linked.
Abstract: We describe a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations. We assume a model in which there are K populations (where K may be unknown), each of which is characterized by a set of allele frequencies at each locus. Individuals in the sample are assigned (probabilistically) to populations, or jointly to two or more populations if their genotypes indicate that they are admixed. Our model does not assume a particular mutation process, and it can be applied to most of the commonly used genetic markers, provided that they are not closely linked. Applications of our method include demonstrating the presence of population structure, assigning individuals to populations, studying hybrid zones, and identifying migrants and admixed individuals. We show that the method can produce highly accurate assignments using modest numbers of loci— e.g. , seven microsatellite loci in an example using genotype data from an endangered bird species. The software used for this article is available from http://www.stats.ox.ac.uk/~pritch/home.html.
27,454 citations
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01 Jan 1981TL;DR: In this paper, the basic theory of Maximum Likelihood Estimation (MLE) is used to detect a difference between two different proportions of a given proportion in a single proportion.
Abstract: Preface.Preface to the Second Edition.Preface to the First Edition.1. An Introduction to Applied Probability.2. Statistical Inference for a Single Proportion.3. Assessing Significance in a Fourfold Table.4. Determining Sample Sizes Needed to Detect a Difference Between Two Proportions.5. How to Randomize.6. Comparative Studies: Cross-Sectional, Naturalistic, or Multinomial Sampling.7. Comparative Studies: Prospective and Retrospective Sampling.8. Randomized Controlled Trials.9. The Comparison of Proportions from Several Independent Samples.10. Combining Evidence from Fourfold Tables.11. Logistic Regression.12. Poisson Regression.13. Analysis of Data from Matched Samples.14. Regression Models for Matched Samples.15. Analysis of Correlated Binary Data.16. Missing Data.17. Misclassification Errors: Effects, Control, and Adjustment.18. The Measurement of Interrater Agreement.19. The Standardization of Rates.Appendix A. Numerical Tables.Appendix B. The Basic Theory of Maximum Likelihood Estimation.Appendix C. Answers to Selected Problems.Author Index.Subject Index.
16,435 citations
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TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Abstract: Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Availability: http://www.broad.mit.edu/mpg/haploview/
Contact: jcbarret@broad.mit.edu
13,862 citations
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TL;DR: In this article, categorical data analysis was used for categorical classification of categorical categorical datasets.Categorical Data Analysis, categorical Data analysis, CDA, CPDA, CDSA
Abstract: categorical data analysis , categorical data analysis , کتابخانه مرکزی دانشگاه علوم پزشکی تهران
10,964 citations