Candidate genes showing no evidence for association or linkage with Alzheimer's disease using family-based methodologies
Lars BertramDeborah BlackerAdam S. CrystalKristina MullinDevon B. KeeneyJennifer JonesS BasuStephen YhuSuzanne Y. GuénetteMelvin G. McInnisRodney C.P. GoRudolph E. Tanzi
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Keywords:
Linkage Disequilibrium
Transmission disequilibrium test
Candidate gene
Genetic linkage
Genetic Association
Abstract Genes that contribute to complex genetic diseases can sometimes be identified by studies that show genetic linkage, or association, with marker genes. The transmission/disequilibrium test is a procedure that tests for the simultaneous presence of these two genetic phenomena.
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Population-wide associations between loci due to linkage disequilibrium can be used to map quantitative trait loci (QTL) with high resolution. However, spurious associations between markers and QTL can also arise as a consequence of population stratification. Statistical methods that cannot differentiate between loci associations due to linkage disequilibria from those caused in other ways can render false-positive results. The transmission-disequilibrium test (TDT) is a robust test for detecting QTL. The TDT exploits within-family associations that are not affected by population stratification. However, some TDTs are formulated in a rigid form, with reduced potential applications. In this study we generalize TDT using mixed linear models to allow greater statistical flexibility. Allelic effects are estimated with two independent parameters: one exploiting the robust within-family information and the other the potentially biased between-family information. A significant difference between these two parameters can be used as evidence for spurious association. This methodology was then used to test the effects of the fourth melanocortin receptor (MC4R) on production traits in the pig. The new analyses supported the previously reported results; i.e., the studied polymorphism is either causal or in very strong linkage disequilibrium with the causal mutation, and provided no evidence for spurious association.
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Linkage and association studies in complex diseases are used to identify and fine map disease loci. The process of identifying the aetiological polymorphism, the molecular variant responsible for the linkage and association of the chromosome region with disease, is complicated by the low penetrance of the disease variant, the linkage disequilibrium between physically‐linked polymorphic markers flanking the disease variant, and the possibility that more than one polymorphism in the most associated region is aetiological. It is important to be able to detect additional disease determinants in a region containing a cluster of genes, such as the major histocompatibility complex (MHC) region on chromosome 6p21. Some methods have been developed for detection of additional variants, such as the Haplotype Method, Marker Association Segregation Chi‐squares (MASC) Method, and the Homozygous Parent Test. Here, the Extended Transmission/Disequilibrium Test is adapted to test for association conditional on a previously associated locus. This test is referred to as the Conditional Extended TDT (CETDT). We discuss the advantages of the CETDT compared to existing methods and, using simulated data, investigate the effect of polymorphism, inheritance, and linkage disequilibrium on the CETDT.
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Abstract The transmission/disequilibrium test (TDT) can be utilized as a test of linkage between a marker and a disease locus or as a test of association between these loci. It relies on the marker information from triads consisting of parents and their affected child. Its properties depend on the purpose it is used for. Its validity for stratified populations makes it particularly attractive. Also, it is often more powerful than allele‐sharing methods for complex diseases.
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SummaryLinkage analysis with genetic markers has been successful in the localization of genes for many monogenic human diseases. In studies of complex diseases, however, tests that rely on linkage disequilibrium (the simultaneous presence of linkage and association) are often more powerful than those that rely on linkage alone. This advantage is illustrated by the transmission/disequilibrium test (TDT). The TDT requires data (marker genotypes) for affected individuals and their parents; for some diseases, however, data from parents may be difficult or impossible to obtain. In this article, we describe a method, called the "sib TDT" (or "S-TDT"), that overcomes this problem by use of marker data from unaffected sibs instead of from parents, thus allowing application of the principle of the TDT to sibships without parental data. In a single collection of families, there might be some that can be analyzed only by the TDT and others that are suitable for analysis by the S-TDT. We show how all the data may be used jointly in one overall TDT-type procedure that tests for linkage in the presence of association. These extensions of the TDT will be valuable for the study of diseases of late onset, such as non–insulin-dependent diabetes, cardiovascular diseases, and other diseases associated with aging. Linkage analysis with genetic markers has been successful in the localization of genes for many monogenic human diseases. In studies of complex diseases, however, tests that rely on linkage disequilibrium (the simultaneous presence of linkage and association) are often more powerful than those that rely on linkage alone. This advantage is illustrated by the transmission/disequilibrium test (TDT). The TDT requires data (marker genotypes) for affected individuals and their parents; for some diseases, however, data from parents may be difficult or impossible to obtain. In this article, we describe a method, called the "sib TDT" (or "S-TDT"), that overcomes this problem by use of marker data from unaffected sibs instead of from parents, thus allowing application of the principle of the TDT to sibships without parental data. In a single collection of families, there might be some that can be analyzed only by the TDT and others that are suitable for analysis by the S-TDT. We show how all the data may be used jointly in one overall TDT-type procedure that tests for linkage in the presence of association. These extensions of the TDT will be valuable for the study of diseases of late onset, such as non–insulin-dependent diabetes, cardiovascular diseases, and other diseases associated with aging.
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Abstract The aim of this study is to compare the power of the transmission disequilibrium test (TDT) to that of the identity‐by‐descent (IBD) distribution test. The relative powers of these tests depend both on the underlying genetic model and on the available family data. Families with two affected sibs are always more informative than those with one affected child and one unaffected child. The IBD test is always more powerful in the first situation and, contrary to the TDT, is independent of the presence of gametic disequilibrium. When there is strong linkage disequilibrium, the TDT can be more powerful than the IBD test. In that case, linkage can be detected by the TDT even in families with only one affected child. ©1995 Wiley‐Liss, Inc.
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Abstract The transmission/disequilibrium test (TDT) can be utilized as a test of linkage between a marker and a disease locus or as a test of association between these loci. It relies on the marker information from triads consisting of parents and their affected child. Its properties depend on the purpose it is used for. Its validity for stratified populations makes it particularly attractive. Also, it is often more powerful than allele‐sharing methods for complex diseases.
Transmission disequilibrium test
Linkage Disequilibrium
Disequilibrium
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Transmission disequilibrium test
Linkage Disequilibrium
Disequilibrium
Linkage (software)
Genetic Association
Association (psychology)
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