Recent methodological developments for a Hardy-Weinberg analysis of X-chromosomal variants

Author

Graffelman, J.; Weir, B.; Ginebra, J.; Puig, X.

Type of activity

Presentation of work at congresses

Name of edition

International Biometric Conference

Date of publication

2018

Presentation's date

2018-07-12

Book of congress proceedings

Proceedings' Book IBC Barcelona 2018

First page

314

Last page

314

Abstract

Hardy-Weinberg equilibrium is a fundamental genetic principle, and assumed in many methods in statistical genetics. Genome-wide genetic studies typically test millions of genetic variants for equilibrium by exact test procedures, as part of a quality control procedure. X-chromosomal variants, for which males have only one copy, have hitherto been analysed by testing equilibrium in females only. This discards one third of the X chromosomes of the sample, and ignores the fact that equilibrium may ...

Hardy-Weinberg equilibrium is a fundamental genetic principle, and assumed in many methods in statistical genetics. Genome-wide genetic studies typically test millions of genetic variants for equilibrium by exact test procedures, as part of a quality control procedure. X-chromosomal variants, for which males have only one copy, have hitherto been analysed by testing equilibrium in females only. This discards one third of the X chromosomes of the sample, and ignores the fact that equilibrium may not hold due to differences in allele frequencies between the sexes. Exact, chi-square and permutation procedures that include males, and that jointly test Hardy-Weinberg proportions and equality of allele frequencies in the sexes, have therefore been developed (Graffelman & Weir, 2016). For the autosomes, the equality of allele frequencies is usually assumed, but a similar joint testing framework can be designed (Graffelman & Weir, 2017). Recently, the joint exact procedure has been extended to the case of multiple alleles, which poses important computational challenges due to the increased number of tables of possible outcomes (Graffelman & Weir, 2017). The joint consideration of equilibrium proportions and allele frequencies of both sexes implies several possible scenarios for a genetic variant. These scenarios are conveniently displayed in ternary diagrams that stratify for gender. The multiple scenarios can be compared by a pairwise likelihood ratio approach, or by Bayesian test procedures (Puig, Ginebra & Graffelman, 2017). Some examples of the new methods, using data from the 1,000 genomes project, are presented. References: Graffelman, J. and Weir, B.S. (2016) Testing for Hardy-Weinberg equilibrium at biallelic genetic markers on the X chromosome. Heredity 116(6): 558-568. doi: 10.1038/hdy.2016.20 Graffelman, J. and Weir, B.S. (2017) On the testing of Hardy-Weinberg proportions and equality of allele frequencies in males and females at bi-allelic genetic markers. Genetic Epidemiology 1-15. doi: http://dx.doi.org/10.1002/gepi.22079 Puig, X., Ginebra, J. and Graffelman, J. (2017) A Bayesian test for Hardy-Weinberg equilibrium of bi-allelic X-chromosomal markers. Heredity. doi: 10.1038/hdy.2017.30 Graffelman, J. and Weir, B.S. (2017) Multi-allelic exact tests for Hardy-Weinberg equilibrium that account for gender. Molecular Ecology Resources. doi: 10.1111/1755-0998.12748