Family-Based Tests of Association in the Presence of Linkage

Department of Biostatistics, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 01/2001; 67(6):1515-25. DOI: 10.1086/316895
Source: PubMed

ABSTRACT Linkage analysis may not provide the necessary resolution for identification of the genes underlying phenotypic variation. This is especially true for gene-mapping studies that focus on complex diseases that do not exhibit Mendelian inheritance patterns. One positional genomic strategy involves application of association methodology to areas of identified linkage. Detection of association in the presence of linkage localizes the gene(s) of interest to more-refined regions in the genome than is possible through linkage analysis alone. This strategy introduces a statistical complexity when family-based association tests are used: the marker genotypes among siblings are correlated in linked regions. Ignoring this correlation will compromise the size of the statistical hypothesis test, thus clouding the interpretation of test results. We present a method for computing the expectation of a wide range of association test statistics under the null hypothesis that there is linkage but no association. To standardize the test statistic, an empirical variance-covariance estimator that is robust to the sibling marker-genotype correlation is used. This method is widely applicable: any type of phenotypic measure or family configuration can be used. For example, we analyze a deletion in the A2M gene at the 5' splice site of "exon II" of the bait region in Alzheimer disease (AD) discordant sibships. Since the A2M gene lies in a chromosomal region (chromosome 12p) that consistently has been linked to AD, association tests should be conducted under the null hypothesis that there is linkage but no association.

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    ABSTRACT: We propose a new method for family-based tests of association and linkage called transmission/disequilibrium tests incorporating unaffected offspring (TDTU). This new approach, constructed based on transmission/disequilibrium tests for quantitative traits (QTDT), provides a natural extension of the transmission/disequilibrium test (TDT) to utilize transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. TDTU can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. When the study sample contains only case-parent trios, the TDTU is equivalent to TDT. Informative-transmission disequilibrium test (i-TDT) and generalized disequilibrium test(GDT) are another two methods that can use information of both unaffected offspring and affected offspring. In contract to i-TDT and GDT, the test statistic of TDTU is simpler and more explicit, and can be implemented more easily. Through computer simulations, we demonstrate that power of the TDTU is slightly higher compared to i-TDT and GDT. All the three methods are more powerful than method that uses affected offspring only, suggesting that unaffected siblings also provide information about linkage and association.
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    ABSTRACT: Autoimmune thyroid disease (AITD), including Graves‘ disease (GD) and Hashimoto thyroiditis (HT), is caused by multiple genetic and environmental factors. The PDS gene (7q31), responsible for Pendred syndrome (congenital sensorineural hearing loss and goitre), encodes a transmembrane protein known as pendrin. Pendrin is an apical porter of iodide in the thyroid. To evaluate the contribution of the PDS gene in susceptibility to AITD, we examined four microsatellite markers in the chromosomal region. One hundred ninety five unrelated patients (GD,141; HT, 54), fifteen multiplex AITD families (104 individuals/46 patients) and 154 normal controls were genotyped. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with GD (p= 10-3) and HT (p= 1.07x10-2) respectively. A family based association test (FBAT) showed significant association and linkage between AITDs and alleles 121bp of D7S496 and 173bp of D7S501. Results obtained by TDT are in good agreement with those obtained by FBAT; linkage and association of the 121 bp allele of D7S496 with AITD was confirmed (p=0.0114). Multipoint non parametric linkage analysis using MERLIN showed intriguing evidence for linkage with marker D7S496 in families with only GD patients (Z=2.12, LOD=0.81, p=0.02). Single point and Multipoint parametric LOD score linkage analysis was also performed. The highest multipoint parametric LOD score was found for marker D7S496 (LOD=1.23; p=0.0086) in families segregating for GD under a dominant model. This work suggest that the PDS gene should be considered a new susceptibility gene to AITDs with varying contribution in each pathology
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