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Accounting for linkage in family-based tests of association with missing parental genotypes.

Publication ,  Journal Article
Martin, ER; Bass, MP; Hauser, ER; Kaplan, NL
Published in: Am J Hum Genet
November 2003

In studies of complex diseases, a common paradigm is to conduct association analysis at markers in regions identified by linkage analysis, to attempt to narrow the region of interest. Family-based tests for association based on parental transmissions to affected offspring are often used in fine-mapping studies. However, for diseases with late onset, parental genotypes are often missing. Without parental genotypes, family-based tests either compare allele frequencies in affected individuals with those in their unaffected siblings or use siblings to infer missing parental genotypes. An example of the latter approach is the score test implemented in the computer program TRANSMIT. The inference of missing parental genotypes in TRANSMIT assumes that transmissions from parents to affected siblings are independent, which is appropriate when there is no linkage. However, using computer simulations, we show that, when the marker and disease locus are linked and the data set consists of families with multiple affected siblings, this assumption leads to a bias in the score statistic under the null hypothesis of no association between the marker and disease alleles. This bias leads to an inflated type I error rate for the score test in regions of linkage. We present a novel test for association in the presence of linkage (APL) that correctly infers missing parental genotypes in regions of linkage by estimating identity-by-descent parameters, to adjust for correlation between parental transmissions to affected siblings. In simulated data, we demonstrate the validity of the APL test under the null hypothesis of no association and show that the test can be more powerful than the pedigree disequilibrium test and family-based association test. As an example, we compare the performance of the tests in a candidate-gene study in families with Parkinson disease.

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Published In

Am J Hum Genet

DOI

ISSN

0002-9297

Publication Date

November 2003

Volume

73

Issue

5

Start / End Page

1016 / 1026

Location

United States

Related Subject Headings

  • Software
  • Siblings
  • Research Design
  • Polymorphism, Single Nucleotide
  • Pedigree
  • Parkinson Disease
  • Parents
  • Models, Genetic
  • Male
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Martin, E. R., Bass, M. P., Hauser, E. R., & Kaplan, N. L. (2003). Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Hum Genet, 73(5), 1016–1026. https://doi.org/10.1086/378779
Martin, Eden R., Meredyth P. Bass, Elizabeth R. Hauser, and Norman L. Kaplan. “Accounting for linkage in family-based tests of association with missing parental genotypes.Am J Hum Genet 73, no. 5 (November 2003): 1016–26. https://doi.org/10.1086/378779.
Martin ER, Bass MP, Hauser ER, Kaplan NL. Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Hum Genet. 2003 Nov;73(5):1016–26.
Martin, Eden R., et al. “Accounting for linkage in family-based tests of association with missing parental genotypes.Am J Hum Genet, vol. 73, no. 5, Nov. 2003, pp. 1016–26. Pubmed, doi:10.1086/378779.
Martin ER, Bass MP, Hauser ER, Kaplan NL. Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Hum Genet. 2003 Nov;73(5):1016–1026.
Journal cover image

Published In

Am J Hum Genet

DOI

ISSN

0002-9297

Publication Date

November 2003

Volume

73

Issue

5

Start / End Page

1016 / 1026

Location

United States

Related Subject Headings

  • Software
  • Siblings
  • Research Design
  • Polymorphism, Single Nucleotide
  • Pedigree
  • Parkinson Disease
  • Parents
  • Models, Genetic
  • Male
  • Humans