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BRASS: Permutation methods for binary traits in genetic association studies with structured samples.

Joelle Mbatchou1,2, Mark Abney3, Mary Sara McPeek2,3

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We developed BRASS, a new permutation method for binary traits in genetic association studies. BRASS controls type 1 error in structured samples, outperforming existing methods and identifying novel associations for canine diseases.

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Area of Science:

  • Genetics
  • Statistical Genetics
  • Bioinformatics

Background:

  • Permutation testing is crucial for significance assessment in genetic association studies when test statistic distributions are unknown.
  • Existing methods like MVNpermute are unsuitable for binary traits in structured samples, leading to inflated type 1 error.
  • Accurate statistical methods are needed for complex trait association mapping in populations with structure and relatedness.

Purpose of the Study:

  • To introduce BRASS (Binary trait Resampling for Association Studies), a novel permutation method for binary traits in genetic association analysis.
  • To evaluate BRASS's performance in controlling type 1 error in complex scenarios, including population structure and familial relatedness.
  • To demonstrate BRASS's utility in identifying significant genetic associations for complex diseases in real-world datasets.

Main Methods:

  • BRASS models sample structure, covariates, ascertainment, and allows simultaneous testing of multiple markers for binary traits.
  • The method accommodates various test statistics and was compared against six other permutation and resampling-based approaches.
  • Simulations incorporated population structure, familial relatedness, ascertainment, and phenotype model misspecification.

Main Results:

  • BRASS demonstrated superior control of type 1 error compared to six other methods across various challenging scenarios.
  • The method successfully identified known genetic associations for elbow dysplasia and idiopathic epilepsy in domestic dogs.
  • BRASS detected a novel significant association for elbow dysplasia on chromosome 35, missed by previous analyses.

Conclusions:

  • BRASS is a robust and effective permutation method for genetic association mapping of binary traits in structured samples.
  • The method offers improved type 1 error control, enhancing the reliability of genetic association findings.
  • BRASS has practical utility, as evidenced by its application in identifying novel disease-associated variants in canine populations.