Disease association by stratification

Abstract

Pathogenetic allele variants that predispose to a disease can be identified by stratifying affected sib pairs by allele-sharing statuss at two or more candidate loci. This locus stratification method has been used to identify an allelic variant at the ATM locus which is implicated in breast cancer.

1 . A method for rapidly identifying pathogenetic allele variants present in the population-at-large that predispose to a disease or that are relevant to diagnosis, prognosis or treatment of a disease which comprises: 
 (a) stratifying sib pairs who have the disease by allele-sharing status at a first candidate locus to identify subgroups of cases bearing potentially pathogenetic alleles of that candidate locus, and    (b) further stratifying the sib pairs by allele-sharing status at a second candidate locus that may demonstrate an epistatic interaction with the first candidate locus.    
     
     
         2 . The method of  claim 1 , which additionally comprises the step of further stratifying the sib pairs by allele-sharing status at a third candidate locus that may demonstrate an epistatic interaction with the first or second candidate locus.  
     
     
         3 . The method of  claim 1 , wherein the sib pairs have cancer.  
     
     
         4 . The method of  claim 2 , wherein the sib pairs have cancer.  
     
     
         5 . The method of  claim 3 , wherein the sib pairs have breast cancer.  
     
     
         6 . The method of  claim 4 , wherein the sib pairs have breast cancer.  
     
     
         7 . The method of  claim 5 , wherein the first candidate locus is the HRAS1 minisatellite locus and the second candidate locus is the ATM locus.  
     
     
         8 . The method of  claim 6 , wherein the first candidate locus is the HRAS1 minisatellite locus, the second candidate locus is the ATM locus, and the third candidate locus is the CDKN1A locus.