Implementing a Unified Approach Tests of Association to family-based tests of association

Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Genetic Epidemiology (Impact Factor: 2.6). 01/2000; 19 Suppl 1(S1):S36-42. DOI: 10.1002/1098-2272(2000)19:1+<::AID-GEPI6>3.0.CO;2-M
Source: PubMed


We describe a broad class of family-based association tests that are adjusted for admixture; use either dichotomous or measured phenotypes; accommodate phenotype-unknown subjects; use nuclear families, sibships or a combination of the two, permit multiple nuclear families from a single pedigree; incorporate di- or multi-allelic marker data; allow additive, dominant or recessive models; and permit adjustment for covariates and gene-by-environment interactions. The test statistic is basically the covariance between a user-specified function of the genotype and a user-specified function of the trait. The distribution of the statistic is computed using the appropriate conditional distribution of offspring genotypes that adjusts for admixture.

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    • "In the initial genomic screen, model-independent linkage analyses were performed with SIBPAL (S.A.G.E., version 4.5) to screen for linkage between the trait and each marker in the AD subgroup [14] [29]. Fine-mapping data generated with custom SNP panels were evaluated using model-independent multipoint linkage analyses and association analyses, including SIBPAL (S.A.G.E., version 6.2.0) and FBAT, for the 95 families determined to be most likely to exhibit an AD mode of inheritance and also for the subset of 13 trios chosen for further sequencing [30] [31] [32]. "
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    ABSTRACT: A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the TBX6 gene and Familial Idiopathic Scoliosis (FIS). To determine if variants within exons of the TBX6 gene segregate with the FIS phenotype within a sample of families with FIS. Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The TBX6 gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the TBX6 gene. Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the TBX6 gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p. Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the TBX6 variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element. Although this study did not identify any TBX6 coding variants that segregate with FIS, we identified a variant that is located in a potential TBX6 enhancer element. Therefore, further investigation of the region is needed.
    Full-text · Article · Jul 2015
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    • "Allelic distribution was found to be in Hardy–Weinberg equilibrium for all alleles. The familybased association test (FBAT) [15] programme was used to examine the association of quantitative traits with the genotype and haplotype . Using the formulae described by Purcell et al. [16] for case– control studies, power was >80% for all TNF-α polymorphisms, under the dominant model for the minor allele. "
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    ABSTRACT: The pro-inflammatory cytokines, TNF-α, IL-6, and IL-8 are elevated in obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Cytokine gene interactions are complex and haplotype analysis may be more informative. We hypothesized that the effects of TNF-α in OSAHS might be due to linkage disequilibrium of the TNF-α (-308A) single nucleotide polymorphism (SNP) with other polymorphisms within the TNF-α gene, and that predisposition to elevated IL-6 and IL-8 levels in OSAHS might be attributable to pro-inflammatory IL-6 and IL-8 gene promoter polymorphisms. 173 subjects were classified as having definite OSAHS or not on the basis of apnoea-hypopnoea frequency, sex, age, and symptoms. Population controls comprised 192 random UK blood donors. Genotyping was undertaken for the TNF- α promoter polymorphisms (-1031, -863, -857, -238), two lymphotoxin-α polymorphisms (intron 1 and Thr60Asn), the pro-inflammatory IL-6 gene promoter polymorphism (-174), and IL-8 gene promoter polymorphisms (-251; -781). There was no significant difference between groups re: genotype/allelic frequency in the genes investigated. Association between disease status and the TNF-α alleles independently (TNF-103, TNF-803, TNF-857, TNF-238) with five haplotypes of TNF-α was not significant (p > 0.05). There was no difference in allelic or genotypic frequencies between obese and non-obese subjects with OSAHS. The TNF- α (-863A) allele alone, was significantly associated with obesity (OR 2.4; CI95% 1.1-5; p = 0.025). Only the TNF- α (308A) SNP appears to be significantly associated with OSAHS. The impact of cytokine gene polymorphisms on phenotypic expression of inflammation in OSAHS is likely to be complex. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Apr 2015 · Sleep Medicine
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    • "As data sets get larger , Mega2's support of the PLINK binary format, both as input and output, is important because it is a common way of compactly storing large scale data and provides a succinct way to efficiently get large scale data into and out of Mega2. Recently, seven new output formats have been added (see Table 1): (1) IQLS/Idcoefs171819-a program for carrying out haplotype-based association tests while properly accounting for relatedness; (2) FBAT[20]– a program for carrying out family-based association tests; (3) Morgan[21]– a package capable of many analyses, with particular strengths in the area of Monte Carlo Markov Chain analyses of family data; (4) Beagle[22]– a package capable of many analyses, including haplotyping and association testing; (5) Eigenstrat[23,24]– a program for inferring and adjusting for population substructure from genome-wide marker data while testing for association; (6) Structure[25,26]– a program for investigating population structure and admixture using genome-wide marker data; and (7) PLINK/SEQ[27]– a package for analysis of data from large-scale sequencing projects. The Mega2 distribution package has been updated to provide greater ease of installation and compatibility with many Unix environments. "
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    ABSTRACT: In a typical study of the genetics of a complex human disease, many different analysis programs are used, to test for linkage and association. This requires extensive and careful data reformatting, as many of these analysis programs use differing input formats. Writing scripts to facilitate this can be tedious, time-consuming, and error-prone. To address these issues, the open source Mega2 data reformatting program provides validated and tested data conversions from several commonly-used input formats to many output formats. Mega2, the Manipulation Environment for Genetic Analysis, facilitates the creation of analysis-ready datasets from data gathered as part of a genetic study. It transparently allows users to process genetic data for family-based or case/control studies accurately and efficiently. In addition to data validation checks, Mega2 provides analysis setup capabilities for a broad choice of commonly-used genetic analysis programs. First released in 2000, Mega2 has recently been significantly improved in a number of ways. We have rewritten it in C++ and have reduced its memory requirements. Mega2 now can read input files in LINKAGE, PLINK, and VCF/BCF formats, as well as its own specialized annotated format. It supports conversion to many commonly-used formats including SOLAR, PLINK, Merlin, Mendel, SimWalk2, Cranefoot, IQLS, FBAT, MORGAN, BEAGLE, Eigenstrat, Structure, and PLINK/SEQ. When controlled by a batch file, Mega2 can be used non-interactively in data reformatting pipelines. Support for genetic data from several other species besides humans has been added. By providing tested and validated data reformatting, Mega2 facilitates more accurate and extensive analyses of genetic data, avoiding the need to write, debug, and maintain one's own custom data reformatting scripts. Mega2 is freely available at
    Full-text · Article · Dec 2014 · Source Code for Biology and Medicine
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