Combining the Sibling Disequilibrium Test and Transmission/Disequilibrium Test for Multiallelic Markers

The American Journal of Human Genetics (Impact Factor: 10.93). 07/1999; 64(6):1785-6. DOI: 10.1086/302421
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    • "Thus, our analyses focused on these haplotypes, rather than the individual SNPs, although TNF À308 was also assessed to enable direct comparison to the results of Boin et al. [2001]. Two types of analyses were conducted within the four sampled populations: (1) a case-control comparison of the TNF haplotypes using CLUMP [Sham and Curtis, 1995a] and (2) the SDT test [Curtis et al., 1999], both of which output appropriately calculated P-values. We chose to use the CLUMP ''T4'' statistic which compares the combined alleles over-represented in the case group with the remainder, allowing a form of w 2 -test with one-degree of freedom in which the inherently two-tailed significance is assessed using Monte–Carlo simulations (CLUMP manual). "
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    ABSTRACT: A single nucleotide polymorphism (TNF-308A) within the promoter region of the gene encoding tumor necrosis factor (TNF), has been significantly associated with schizophrenia in a study of Italian patients and control subjects Boin et al. [2001: Mol Psychiatry 6:79-82]. We have applied case-control analyses to examine TNF promoter haplotypes (containing TNF -308 and two additional promoter variants: TNF-376 and TNF-238) in four schizophrenia cohorts drawn from Australian, Indian Fijian, Indigenous Fijian, and Brahmin populations. In addition, we have applied the sibling transmission disequilibrium (STD) test to promoter haplotypes within 81 trios drawn from Australian Caucasian pedigrees with multiple schizophrenia cases, and 86 trios drawn from the Brahmin population of Tamil Nadu province in Southern India. Within each of these cohorts, we found no evidence of recombination between these tightly linked promoter variants, supporting previous studies which demonstrated that only a subset of the eight possible haplotypes exist. Of the four observed haplotypes, we and others have observed only one carries the TNF-308A variant allele. We report no significant differences in TNF promoter haplotype frequencies between the patient and control groups within each population, although the Indian Fijian cohort showed a trend towards reduced TNF-308A alleles amongst schizophrenia cases (P = 0.07). We found no evidence of bias in TNF promoter haplotype transmission to schizophrenia probands. Very similar results were obtained when only the TNF-308 polymorphism was considered. Taken together, these data provide no support for the involvement of TNF promoter variants TNF-308, TNF-376, and TNF-238 in schizophrenia susceptibility within four ethnically distinct cohorts.
    Full-text · Article · Aug 2003 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    ABSTRACT: Previously we obtained modest linkage evidence implicating 17q11. 1-12 in bipolar disorder. A modified genome screen, based on gene-rich regions, on a collection of Irish sib-pair nuclear families revealed excess allele sharing at markers flanking the gene encoding the serotonin transporter (5-HTT; hSERT). Here we describe a study designed to combine the advantages of family-based association studies with the consideration of multiple polymorphic markers within a candidate gene. Ninety-two Irish families, with a total of 106 proband-parent trios, have been genotyped for 3 previously known polymorphisms within hSERT (5-HTTLPR, intron 2 VNTR, and 3' UTR G/T). Data from two and three polymorphic marker haplotypes revealed a number of marker combinations that showed evidence supportive of association; the most significant being for polymorphisms 5-HTTLPR and 3' UTR G/T (global chi(2), 12.91, df 3, P = 0.005). In addition, modest evidence of association also was observed for 5-HTTLPR alone. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:845-849, 2000.
    No preview · Article · Jan 2001 · American Journal of Medical Genetics
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    ABSTRACT: Over the past decade, attention has turned from positional cloning of Mendelian disease genes to the dissection of complex diseases. Both theoretical and empirical studies have shown that traditional linkage studies may be inferior in power compared to studies that directly utilize allele status. Case-control association studies, as an alternative, are subject to bias due to population stratification. As a compromise between linkage studies and case-control studies, family-based association designs have received great attention recently due to their potentially higher power to identify complex disease genes and their robustness in the presence of population substructure. In this review, we first describe the basic family-based association design involving one affected offspring with its two parents, all genotyped for a biallelic genetic marker. Extensions of the original transmission disequilibrium tests to multiallelic markers, families with multiple siblings, families with incomplete parental genotypes, and general pedigree structures are discussed. Further developments of statistical methods to study quantitative traits, to analyse genes on the X chromosome, to incorporate multiple tightly linked markers, to identify imprinting genes, and to detect gene-environment interactions are also reviewed. Finally, we discuss the implications of the completion of the Human Genome Project and the identification of hundreds of thousands of genetic polymorphisms on employing family-based association designs to search for complex disease genes.
    Preview · Article · Jan 2001 · Statistical Methods in Medical Research
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