Implementing a Unified Approach Tests of Association to family-based tests of association
ABSTRACT 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.
- SourceAvailable from: Cristina M Justice
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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  . 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   . "
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.07/2015; 3(4). DOI:10.1016/j.jspd.2015.01.005
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- "Allelic distribution was found to be in Hardy–Weinberg equilibrium for all alleles. The familybased association test (FBAT)  programme was used to examine the association of quantitative traits with the genotype and haplotype . Using the formulae described by Purcell et al.  for case– control studies, power was >80% for all TNF-α polymorphisms, under the dominant model for the minor allele. "
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.Sleep Medicine 04/2015; 16(6). DOI:10.1016/j.sleep.2015.01.006 · 3.15 Impact Factor
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- "We used the FBAT software (Laird et al., 2000) to test for association between the gene polymorphism and the disease under " biallelic " , " additive " and " recessive " model. Meanwhile, the global haplotype tests of association were performed under " multiallelic " mode in HBAT. "
ABSTRACT: Autoimmune thyroid diseases (AITD), which include Hashimoto thyroiditis (HT), Graves' disease (GD) and primary idiopathic myxoedema (PIM), are recognized by their clinical and genetic heterogeneity. In this study, we have carried on a global approach gathering 20 year genetic and clinical data on a Tunisian multigenerational family (Akr). Our purpose was search for a combined genotype involved in AITD susceptibility using 33 gene polymorphisms. The Akr pedigree is composed of more than 400 members distributed on 10 generations. Clinical follow-up was performed by appreciation of the thyroid gland and measurement of both thyroid hormone and auto antibody levels. We used FBAT software to test for association between gene polymorphisms and AITDs. Clinical follow-up has showed that the number of AITD patients has increased from 25 to 78 subjects subdivided on 51 cases of GD, 22 PIM and 5 HT. Concerning genetic analysis, our study has revealed new gene association when compared with our previous analysis (considering single genes). Thus, PTPN22, TG and VDR gene polymorphisms have became associated with p-values ranging from 4.6 10− 2 to 4 10− 3 when considered with other genes on the same chromosome; giving evidence for gene interaction. The most significant association was found with the MHC region (p = 7.15 10− 4). Moreover, and among gene polymorphisms explored, our analysis has identified some of them as AITD biomarkers. Indeed, PDS gene polymorphisms were associated with either exophthalmia or goiter (p-values from 10− 2 to 10− 3). In conclusion, our study gives evidence for gene interaction in AITD development confirming genetic complexity of these diseases.Meta Gene 12/2014; 2(1):63–71. DOI:10.1016/j.mgene.2013.11.003