A Multilocus Model of the Genetic Architecture of Autoimmune Thyroid Disorder, with Clinical Implications

Veronica J. Vieland, Yungui Huang, Christopher Bartlett, Terry F. Davies, Yaron Tomer

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

We report here a preliminary model of the genetic architecture of Autoimmune Thyroid Disorder (AITD). Using a flexible class of mathematical modeling techniques, applied to an established set of data and supplemented with information both from candidate-gene and genome-wide-association studies and from basic bioinformatics, we find strong statistical support for a model in which AITD is the result of "hits" along three distinct genetic pathways: affected individuals have (1) a genetic susceptibility to clinical AITD, along with (2) a separate predisposition to develop the autoantibodies characteristic of AITD, and they also have (3) a predisposition to develop high levels of autoantibodies once they occur. Genes underlying each of these factors then appear to interact with one another to cause clinical AITD. We also find that a genetic variant in CTLA4 that increases risk for AITD in some people might actually protect against AITD in others, depending on which additional risk variants an individual carries. Our data show that the use of statistical methods for the incorporation of information from multiple sources, combined with careful modeling of distinct intermediate phenotypes, can provide insights into the genetic architecture of complex diseases. This model has several clinical implications, which we believe will prove relevant to other complex diseases as well.

Original languageEnglish (US)
Pages (from-to)1349-1356
Number of pages8
JournalAmerican Journal of Human Genetics
Volume82
Issue number6
DOIs
StatePublished - Jun 6 2008
Externally publishedYes

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Genetic Models
Thyroid Gland
Autoantibodies
Genome-Wide Association Study
Genetic Predisposition to Disease
Computational Biology
Genes
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

A Multilocus Model of the Genetic Architecture of Autoimmune Thyroid Disorder, with Clinical Implications. / Vieland, Veronica J.; Huang, Yungui; Bartlett, Christopher; Davies, Terry F.; Tomer, Yaron.

In: American Journal of Human Genetics, Vol. 82, No. 6, 06.06.2008, p. 1349-1356.

Research output: Contribution to journalArticle

Vieland, Veronica J. ; Huang, Yungui ; Bartlett, Christopher ; Davies, Terry F. ; Tomer, Yaron. / A Multilocus Model of the Genetic Architecture of Autoimmune Thyroid Disorder, with Clinical Implications. In: American Journal of Human Genetics. 2008 ; Vol. 82, No. 6. pp. 1349-1356.
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