Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection

Zhehao Zhang, Jen Chyong Wang, William Howells, Peng Lin, Arpana Agrawal, Howard Edenberg, Jay A. Tischfield, Marc A. Schuckit, Laura J. Bierut, Alison Goate, John P. Rice

Research output: Contribution to journalArticle

Abstract

Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this study, we developed a novel approach to "infer" the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure to assess its operating characteristics. We applied the dTDT to the simulated data and documented the power of the dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals. One SNP (rs4903712 on chromosome 14) remained significant after correcting for multiple testing Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data.

Original languageEnglish
Article numbere63526
JournalPLoS One
Volume8
Issue number5
DOIs
StatePublished - May 14 2013

Fingerprint

Linkage Disequilibrium
Single Nucleotide Polymorphism
linkage (genetics)
single nucleotide polymorphism
Polymorphism
Information Storage and Retrieval
Genome-Wide Association Study
dosage
Microsatellite Repeats
Nucleotides
testing
Genes
Chromosomes, Human, Pair 14
Disease Susceptibility
Genetic Markers
microsatellite repeats
Alcoholism
Names
family studies
Alleles

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Zhang, Z., Wang, J. C., Howells, W., Lin, P., Agrawal, A., Edenberg, H., ... Rice, J. P. (2013). Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection. PLoS One, 8(5), [e63526]. https://doi.org/10.1371/journal.pone.0063526

Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection. / Zhang, Zhehao; Wang, Jen Chyong; Howells, William; Lin, Peng; Agrawal, Arpana; Edenberg, Howard; Tischfield, Jay A.; Schuckit, Marc A.; Bierut, Laura J.; Goate, Alison; Rice, John P.

In: PLoS One, Vol. 8, No. 5, e63526, 14.05.2013.

Research output: Contribution to journalArticle

Zhang, Z, Wang, JC, Howells, W, Lin, P, Agrawal, A, Edenberg, H, Tischfield, JA, Schuckit, MA, Bierut, LJ, Goate, A & Rice, JP 2013, 'Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection', PLoS One, vol. 8, no. 5, e63526. https://doi.org/10.1371/journal.pone.0063526
Zhang, Zhehao ; Wang, Jen Chyong ; Howells, William ; Lin, Peng ; Agrawal, Arpana ; Edenberg, Howard ; Tischfield, Jay A. ; Schuckit, Marc A. ; Bierut, Laura J. ; Goate, Alison ; Rice, John P. / Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection. In: PLoS One. 2013 ; Vol. 8, No. 5.
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