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Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
Published on: June 21, 2018
XM: association testing on the X-chromosome in case-control samples with related individuals
Timothy Thornton1, Qian Zhang, Xiaochen Cai
1Department of Biostatistics, University of Washington, Seattle, Washington 98195-7232, USA. tathornt@u.washington.edu
Genetic Epidemiology
|May 4, 2012
Summary
New methods for X-chromosome genetic association analysis in families improve detection of complex traits. These tools account for relatedness and sex differences, successfully identifying a gene linked to alcohol dependence.
Area of Science:
- Genetics
- Statistical Genetics
- Bioinformatics
Background:
- Genetic variants on the X-chromosome are implicated in complex traits, but analytical methods lag behind autosomal markers.
- Detecting associations with X-linked markers in family studies presents unique challenges due to relatedness and sex-specific copy number variations.
Purpose of the Study:
- To develop and validate novel statistical methods for case-control association testing of X-chromosome markers in samples with related individuals.
- To address limitations in existing methods by accounting for familial correlation and sex-specific allele copy numbers.
Main Methods:
- Proposed the XM method for case-control association testing with X-linked markers, adjusting for relatedness and sex differences.
- Developed additional tests (Xχ, XW) and derived the best linear unbiased estimator for X-linked allele frequency.
- Incorporated features such as handling general family/case-control designs, including controls of unknown phenotype, and utilizing phenotype data from relatives with missing genotypes.
Main Results:
- Simulation studies demonstrated the power and validity of the proposed methods in related individuals.
- Applied methods to asthma in Hutterites, showing computational feasibility of XM and robustness of variance estimation.
- Detected a significant association between alcohol dependence and SNP rs979606 in the monoamine oxidases A gene in the GAW 14 COGA data.
Conclusions:
- The developed methods, particularly XM, provide a robust and computationally feasible framework for X-chromosome association studies in family-based designs.
- The findings highlight the importance of considering X-linked genetic factors in complex traits and demonstrate a significant association with a gene relevant to substance abuse.
Related Concept Videos
01:11Genome-wide Association Studies-GWAS
Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
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01:19X-linked Traits
In most mammalian species, females have two X sex chromosomes and males have an X and Y. As a result, mutations on the X chromosome in females may be masked by the presence of a normal allele on the second X. In contrast, a mutation on the X chromosome in males more often causes observable biological defects, as there is no normal X to compensate. Trait variations arising from mutations on the X chromosome are called “X-linked”.
01:19X-linked Traits
In most mammalian species, females have two X sex chromosomes and males have an X and Y. As a result, mutations on the X chromosome in females may be masked by the presence of a normal allele on the second X. In contrast, a mutation on the X chromosome in males more often causes observable biological defects, as there is no normal X to compensate. Trait variations arising from mutations on the X chromosome are called “X-linked”.
02:32X and Y Chromosomes
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02:50Dosage Compensation
In animals, gender is determined by the number and type of sex chromosome. For example, human females have two X chromosomes, and males have one X and one Y chromosome, whereas C.elegans with one X chromosome is a male, and the one with two X chromosomes is a hermaphrodite.
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Normal male Drosophila has a ratio of one X chromosome to two sets of autosomes. In contrast, normal female Drosophila...
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