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Open Access Methodology article

Incorporation of covariates in simultaneous localization of two linked loci using affected relative pairs

Yen-Feng Chiu1*, Jeng-Min Chiou2, Kung-Yee Liang34 and Chun-Yi Lee1

Author Affiliations

1 Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Rd., Zhunan, Miaoli 350, Taiwan

2 Institute of Statistical Science, Academia Sinica, Taipei, Taipei, Taiwan

3 Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, USA

4 National Yang-Ming University, Taipei, Taiwan

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BMC Genetics 2010, 11:67  doi:10.1186/1471-2156-11-67

Published: 14 July 2010



Many dichotomous traits for complex diseases are often involved more than one locus and/or associated with quantitative biomarkers or environmental factors. Incorporating these quantitative variables into linkage analysis as well as localizing two linked disease loci simultaneously could therefore improve the efficiency in mapping genes. We extended the robust multipoint Identity-by-Descent (IBD) approach with incorporation of covariates developed previously to simultaneously estimate two linked loci using different types of affected relative pairs (ARPs).


We showed that the efficiency was enhanced by incorporating a quantitative covariate parametrically or non-parametrically while localizing two disease loci using ARPs. In addition to its help in identifying factors associated with the disease and in improving the efficiency in estimating disease loci, this extension also allows investigators to account for heterogeneity in risk-ratios for different ARPs. Data released from the collaborative study on the genetics of alcoholism (COGA) for Genetic Analysis Workshop 14 (GAW 14) were used to illustrate the application of this extended method.


The simulation studies and example illustrated that the efficiency in estimating disease loci was demonstratively enhanced by incorporating a quantitative covariate and by using all relative pairs while mapping two linked loci simultaneously.