Detection of parent-of-origin effects in nuclear families using haplotype analysis.
Despite the potential pitfalls of stratification, population-based association studies nowadays are being conducted more often than family-based association studies. However, the mechanism of genomic imprinting has lately been implicated in the etiology of genetic complex diseases and can be detected using statistics only in family-based designs. Powerful tests for association and imprinting have been proposed previously for case-parent trios and single markers. Since the power of association studies can be improved if multiple affected children and haplotypes are considered, we extended the parental asymmetry test (PAT) for imprinting to a test that is suited for both general nuclear families and haplotypes, called HAP-PAT. Significance of the HAP-PAT is determined via a Monte-Carlo simulation procedure. In addition to the HAP-PAT, we modified a haplotype-based association test, proposed by us before, in such a way that either only paternal or maternal transmissions contribute to the test statistic. The approaches were implemented in FAMHAP and we evaluated their performance under a variety of disease models. We were able to demonstrate the usefulness of our haplotype-based approaches to detect parent-of-origin effects. Furthermore, we showed that also in the presence of imprinting it is more reasonable to consider all affected children of a nuclear family, than to randomly select one affected child from each family and to conduct a trio study using the selected individuals.
Becker
Tim
T
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. becker@imbie.med.uni-bonn.de
Baur
Max P
MP
Knapp
Michael
M
D003198:Computer Simulation; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D009010:Monte Carlo Method; D009679:Nuclear Family; D010290:Parents
D005819:Genetic Markers