Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees
Laura Almasy,John Blangero +1 more
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TLDR
It is shown how variance-component linkage methods can be used in pedigrees of arbitrary size and complexity, and a general framework for multipoint identity-by-descent (IBD) probability calculations is developed.Abstract:
Multipoint linkage analysis of quantitative-trait loci (QTLs) has previously been restricted to sibships and small pedigrees. In this article, we show how variance-component linkage methods can be used in pedigrees of arbitrary size and complexity, and we develop a general framework for multipoint identity-by-descent (IBD) probability calculations. We extend the sib-pair multipoint mapping approach of Fulker et al. to general relative pairs. This multipoint IBD method uses the proportion of alleles shared identical by descent at genotyped loci to estimate IBD sharing at arbitrary points along a chromosome for each relative pair. We have derived correlations in IBD sharing as a function of chromosomal distance for relative pairs in general pedigrees and provide a simple framework whereby these correlations can be easily obtained for any relative pair related by a single line of descent or by multiple independent lines of descent. Once calculated, the multipoint relative-pair IBDs can be utilized in variance-component linkage analysis, which considers the likelihood of the entire pedigree jointly. Examples are given that use simulated data, demonstrating both the accuracy of QTL localization and the increase in power provided by multipoint analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance component and IBD estimation methods have been implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package.read more
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Journal ArticleDOI
Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia.
Tiffany A. Greenwood,Neal R. Swerdlow,Raquel E. Gur,Kristin S. Cadenhead,Monica E. Calkins,Dorcas J. Dobie,Robert Freedman,Michael F. Green,Ruben C. Gur,Laura C. Lazzeroni,Keith H. Nuechterlein,Ann Olincy,Allen D. Radant,Amrita Ray,Nicholas J. Schork,L.J. Seidman,Larry J. Siever,Jeremy M. Silverman,William S. Stone,Catherine A. Sugar,Debby W. Tsuang,Ming T. Tsuang,Bruce I. Turetsky,Gregory A. Light,David L. Braff +24 more
TL;DR: Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified.
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Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study.
Giuseppina T. Russo,James B. Meigs,L. Adrienne Cupples,Serkalem Demissie,James D. Otvos,Peter W.F. Wilson,Carlos Lahoz,Domenico Cucinotta,Patrick Couture,Tonya Mallory,Ernst J. Schaefer,Jose M. Ordovas +11 more
TL;DR: Despite the described associations with lipid and glucose metabolism related risk factors, the Framingham Offspring Study did not find any significant increase in CHD risk associated with the S2 allele in this population.
Journal ArticleDOI
Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent.
Nicholette D. Palmer,Solomon K. Musani,Laura M. Yerges-Armstrong,Mary F. Feitosa,Lawrence F. Bielak,Ruben Hernaez,Bratati Kahali,J. Jeffrey Carr,Tamara B. Harris,Min A. Jhun,Sharon L.R. Kardia,Carl D. Langefeld,Thomas H. Mosley,Jill M. Norris,Albert V. Smith,Herman A. Taylor,Lynne E. Wagenknecht,Jiankang Liu,Ingrid B. Borecki,Patricia A. Peyser,Elizabeth K. Speliotes +20 more
TL;DR: Multiple genetic variants are associated with hepatic steatosis across ancestries, which explains a substantial proportion of the genetic predisposition in African‐ and Hispanic‐Americans.
Journal ArticleDOI
Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk
Sara Lindström,Deborah J. Thompson,Andrew D. Paterson,Jingmei Li,Gretchen L. Gierach,Christopher G. Scott,Jennifer Stone,Julie A. Douglas,Isabel dos-Santos-Silva,Pablo Fernández-Navarro,Jajini Verghase,Paula Smith,Judith E. Brown,Robert Luben,Nicholas J. Wareham,Ruth J. F. Loos,John A. Heit,V. Shane Pankratz,Aaron D. Norman,Ellen L. Goode,Julie M. Cunningham,Mariza deAndrade,Robert A. Vierkant,Kamila Czene,Peter A. Fasching,Laura Baglietto,Laura Baglietto,Melissa C. Southey,Graham G. Giles,Graham G. Giles,Kaanan P. Shah,Heang Ping Chan,Mark A. Helvie,Andrew H. Beck,Nicholas W. Knoblauch,Aditi Hazra,David J. Hunter,Peter Kraft,Marina Pollán,Jonine D. Figueroa,Fergus J. Couch,John L. Hopper,Per Hall,Douglas F. Easton,Norman F. Boyd,Celine M. Vachon,Rulla M. Tamimi +46 more
TL;DR: The results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes provide further evidence of a shared genetic basis between mammographicdensity and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci.
Journal ArticleDOI
Random-effects Cox proportional hazards model: general variance components methods for time-to-event data.
TL;DR: The correlated frailty models described here can be used to perform genetic analyses, and other analyses with structured random effects, on age‐at‐onset data in a manner analogous to standard variance components methods for quantitative traits, and make computation for correlated time‐to‐event data feasible.
References
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Journal ArticleDOI
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results
Eric S. Lander,Leonid Kruglyak +1 more
TL;DR: Specific standards designed to maintain rigor while also promoting communication are proposed for the interpretation of linkage results in genetic studies under way for many complex traits.
Journal Article
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Asymptotic Properties of Maximum Likelihood Estimators and Likelihood Ratio Tests under Nonstandard Conditions
Steven G. Self,Kung Yee Liang +1 more
TL;DR: In this article, the authors derived the asymptotic distribution of maximum likelihood estimators and likelihood ratio statistics, which is the same as the distribution of the projection of the Gaussian random variable.
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A General Model for the Genetic Analysis of Pedigree Data
TL;DR: Assuming random mating and random sampling of pedigrees, the likelihood of a set of pedigree data is developed in terms of the population distribution of the different genotypes.
Journal ArticleDOI
Construction of multilocus genetic linkage maps in humans.
Eric S. Lander,Philip Green +1 more
TL;DR: Several alternative algorithms for constructing human linkage maps given a specified gene order are described, one of which allows maximum-likelihood multilocus linkage maps for dozens of DNA markers in such three-generation pedigrees to be constructed in minutes.
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