Search for haplotype interactions that influence susceptibility to type 1 diabetes, through use of unphased genotype data

J. Zhang, F.M. Liang, W.R.M. Dassen, P.A. Doevendans, M.C.M. de Gunst

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Type 1 diabetes is a T-cell-mediated chronic disease characterized by the autoimmune destruction of pancreatic insulin-producing β cells and complete insulin deficiency. It is the result of a complex interrelation of genetic and environmental factors, most of which have yet to be identified. Simultaneous identification of these genetic factors, through use of unphased genotype data, has received increasing attention in the past few years. Several approaches have been described, such as the modified transmission/ disequilibrium test procedure, the conditional extended transmission/ disequilibrium test, and the stepwise logistic-regression procedure. These approaches are limited either by being restricted to family data or by ignoring so-called "haplotype interactions" between alleles. To overcome this limit, the present study provides a general method to identify, on the basis of unphased genotype data, the haplotype blocks that interact to define the risk for a complex disease. The principle underpinning the proposal is minimal entropy. The performance of our procedure is illustrated for both simulated and real data. In particular, for a set of Dutch type 1 diabetes data, our procedure suggests some novel evidence of the interactions between and within haplotype blocks that are across chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 15, 16, 17, 19, and 21. The results demonstrate that, by considering interactions between potential disease haplotype blocks, we may succeed in identifying disease-predisposing genetic variants that might otherwise have remained undetected.
Original languageEnglish
Pages (from-to)1385-1401
JournalAmerican Journal of Human Genetics
Volume73
Issue number6
DOIs
Publication statusPublished - 2003

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Type 1 Diabetes Mellitus
Haplotypes
Genotype
Insulin
Inborn Genetic Diseases
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 1
Entropy
Chronic Disease
Logistic Models
Alleles
T-Lymphocytes

Cite this

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title = "Search for haplotype interactions that influence susceptibility to type 1 diabetes, through use of unphased genotype data",
abstract = "Type 1 diabetes is a T-cell-mediated chronic disease characterized by the autoimmune destruction of pancreatic insulin-producing β cells and complete insulin deficiency. It is the result of a complex interrelation of genetic and environmental factors, most of which have yet to be identified. Simultaneous identification of these genetic factors, through use of unphased genotype data, has received increasing attention in the past few years. Several approaches have been described, such as the modified transmission/ disequilibrium test procedure, the conditional extended transmission/ disequilibrium test, and the stepwise logistic-regression procedure. These approaches are limited either by being restricted to family data or by ignoring so-called {"}haplotype interactions{"} between alleles. To overcome this limit, the present study provides a general method to identify, on the basis of unphased genotype data, the haplotype blocks that interact to define the risk for a complex disease. The principle underpinning the proposal is minimal entropy. The performance of our procedure is illustrated for both simulated and real data. In particular, for a set of Dutch type 1 diabetes data, our procedure suggests some novel evidence of the interactions between and within haplotype blocks that are across chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 15, 16, 17, 19, and 21. The results demonstrate that, by considering interactions between potential disease haplotype blocks, we may succeed in identifying disease-predisposing genetic variants that might otherwise have remained undetected.",
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Search for haplotype interactions that influence susceptibility to type 1 diabetes, through use of unphased genotype data. / Zhang, J.; Liang, F.M.; Dassen, W.R.M.; Doevendans, P.A.; de Gunst, M.C.M.

In: American Journal of Human Genetics, Vol. 73, No. 6, 2003, p. 1385-1401.

Research output: Contribution to JournalArticleAcademicpeer-review

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