A permutation procedure for the haplotype method for identification of disease-predisposing variants

Authors
Citation
H. Li, A permutation procedure for the haplotype method for identification of disease-predisposing variants, ANN HUM GEN, 65, 2001, pp. 189-196
Citations number
15
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Molecular Biology & Genetics
Journal title
ANNALS OF HUMAN GENETICS
ISSN journal
0003-4800 → ACNP
Volume
65
Year of publication
2001
Part
2
Pages
189 - 196
Database
ISI
SICI code
0003-4800(200103)65:<189:APPFTH>2.0.ZU;2-U
Abstract
Once a genetic region involved in a complex disease has been localized thro ugh linkage or association studies, we need methods to help is identify the actual disease predisposing genetic variant(s) in the region. A large numb er of single nucleotide polymorphic (SNP) sites may exist in this region. I t is important to identify genetic variants directly involved in disease fr om those in linkage disequilibrium, and thus associated with, the disease p redisposing variant(s). A question of great interest is to test whether a S NP, or a combination of SNPs, that influence the trait under investigation have been identified. For many complex HLA-associated diseases, patterns of amino acid site variability raise the possibility that HLA-variation assoc iation with a disease may not be due to a given allele but rather one or mo re variable amino acid sites occurring on several alleles. Here the questio n is whether an amino acid variant or combination of amino variants involve d in disease are identified. To address this question, this paper proposes a permutation procedure for the haplotype method, to test whether all the s ites involved in the disease have been identified using the haplotypic data of patients and controls. The method is based on the amino acid sites invo lved in the disease process, the relative frequencies of amino acid variant s at sites not involved in disease, but the linkage disequilibrium with the disease-predisposing sites, are expected to be the same in patients and co ntrols. this procedure takes into account the non-independence of the sites sampled and is robust to mode of inheritance and penetrance of the disease and can definitely specify when all the disease predisposing sites have no t been identified. Application to both simulated data and real data sets on type 1 diabetes and alcoholism indicates that the proposed procedure works well in testing the important null hypothesis all the predisposing sites a re identified.