Journal ArticleDOI
Pedigree disequilibrium tests for multilocus haplotypes.
TLDR
A permutation procedure for the null hypothesis of interest is described, which controls for violation of the assumptions, and a likelihood‐ratio test is proposed, using the expectation‐maximization (E‐M) algorithm to account for haplotype ambiguities.Abstract:
Association tests of multilocus haplotypes are of interest both in linkage disequilibrium mapping and in candidate gene studies. For case-parent trios, I discuss the extension of existing multilocus methods to include ambiguous haplotypes in tests of models which distinguish between the cis and trans phase. A likelihood-ratio test is proposed, using the expectation-maximization (E-M) algorithm to account for haplotype ambiguities. Assumptions about the population structure are required, but realistic situations, including population stratification, which violate the assumptions lead to conservative tests. I describe a permutation procedure for the null hypothesis of interest, which controls for violation of the assumptions. For general pedigrees, I describe extensions of the pedigree disequilibrium test to include uncertain haplotypes. The summary statistics are replaced by their expected values over prior distributions of haplotype frequencies. If prior distributions are not available, a valid test is possible by using the E-M algorithm to estimate the null distribution of haplotype frequencies. Similar methods are available for quantitative traits. Exact permutation tests are difficult to construct in small samples, but an approximate procedure is appropriate in large samples, and can be used to account for dependencies between tests of multiple haplotypes and loci.read more
Citations
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A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1
Jochen Hampe,Andre Franke,Philip Rosenstiel,Philip Rosenstiel,Andreas Till,Markus Teuber,Klaus Huse,Mario Albrecht,Gabriele Mayr,Francisco M. De La Vega,Jason C Briggs,Simone Günther,Natalie J. Prescott,Clive M. Onnie,Robert Häsler,Bence Sipos,Ulrich R. Fölsch,Thomas Lengauer,Matthias Platzer,Christopher G. Mathew,Michael Krawczak,Stefan Schreiber +21 more
TL;DR: Data suggest that the underlying biological process may be specific to Crohn disease, and that marker rs2241880, a coding SNP (T300A), carries virtually all the disease risk exerted by the ATG16L1 locus.
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Risk alleles for multiple sclerosis identified by a genomewide study.
David A. Hafler,Alastair Compston,Stephen Sawcer,Mark J. Daly,Philip L. De Jager,Stacey Gabriel,Daniel B. Mirel,Adrian J. Ivinson,Margaret A. Pericak-Vance,Simon G. Gregory,John D. Rioux,John D. Rioux,Jacob L. McCauley,Lisa F. Barcellos,Lisa F. Barcellos,Bruce A.C. Cree,Stephen L. Hauser +16 more
TL;DR: Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.
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Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.
TL;DR: It is shown that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.
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A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder.
Amber E. Baum,Nirmala Akula,Michael Cabanero,Cardona I,Winston Corona,Ben Klemens,Ben Klemens,Thomas G. Schulze,Sven Cichon,Marcella Rietschel,Markus M. Nöthen,Alexander Georgi,Johannes Schumacher,M Schwarz,R Abou Jamra,Susanne Höfels,Peter Propping,Jaya M. Satagopan,Sevilla D. Detera-Wadleigh,John Hardy,Francis J. McMahon +20 more
TL;DR: This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk and may be a polygenic disease.
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Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data.
TL;DR: A novel likelihood for nuclear families is proposed, in which distinct sets of association parameters are used to model the parental genotypes and the offspring genotypes, which is robust to population structure when the data are complete, and has only minor loss of robustness when there are missing data.
References
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Journal Article
Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).
TL;DR: The statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test] is described and the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs is shown.
Journal ArticleDOI
Score Tests for Association between Traits and Haplotypes when Linkage Phase Is Ambiguous
TL;DR: New methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits are developed, which allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits.
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