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A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity

Genes & Immunity volume 3, pages S5–S12 (2002)Cite this article

Abstract

Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22–24, 2q37, 4p16, 12p12–11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11–25, and 20q12 and greatly improved evidence for linkage at 1q22–24, 2q37, 12p12–11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects.

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, OH, USA

    J M Olson, Y Song & D M Dudek

  2. Department of Medicine and Institute of Human Genetics, University of Minnesota Medical School, MN, USA

    K L Moser

  3. Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma, USA

    J A Kelly, G R Bruner, K J Downing, C K Berry, J A James & J B Harley

  4. Department of Medicine, University of Oklahoma and the US Department of Veterans Affairs Medical Center, Oklahoma, USA

    J B Harley

Authors
  1. J M Olson
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  2. Y Song
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  3. D M Dudek
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  4. K L Moser
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  5. J A Kelly
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  6. G R Bruner
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  7. K J Downing
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  8. C K Berry
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  9. J A James
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  10. J B Harley
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Correspondence to J M Olson.

Additional information

This work was supported in part by US Public Health Service grants HG01577 from the National Center for Human Genome Research, RR03655 and RR15577 from the National Center for Research Resources, AR42460 and AR45231 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and AI24717 and AI31584 from the National Institute of Allergy and Infectious Diseases and the US Department of Veterans Affairs. The 101 pedigrees (Cohorts A, B, and C) were obtained from the Lupus Multiplex Registry and Repository (AR52221) (see http://mrf.ouhsc.edu/lupus). Some of the results in this paper were obtained using the program package SAGE, supported by US Public Health Service Resource Grant RR03655 from the National Center for Research Resources.

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Olson, J., Song, Y., Dudek, D. et al. A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity. Genes Immun 3 (Suppl 1), S5–S12 (2002). https://doi.org/10.1038/sj.gene.6363860

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  • DOI: https://doi.org/10.1038/sj.gene.6363860

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