Detection and replication of linkage to a complex human disease

Area of Science:

• Genetics
• Statistical Genetics
• Human Disease Genetics

Background:

• Mapping susceptibility loci for complex human diseases often yields weak, unreproducible linkage evidence.
• The extreme discordant sib pair (EDSP) strategy offers a potential solution by sampling families with extreme trait values for replication studies.

Purpose of the Study:

• To evaluate the effectiveness of EDSP sampling variants in improving linkage evidence for complex diseases.
• To assess the impact of different quantitative trait cutoffs on the success of EDSP-based replication studies.

Main Methods:

• Joint segregation and linkage analysis of four bivariate phenotypes (affection status and a quantitative trait).
• Genomic scan of the GAW10 Problem 2B data set.
• Selection of EDSP families based on quantitative trait (Q2) values at 1%, 2%, 5%, 10%, and 20% cutoffs.

Main Results:

• Suggestive linkage evidence for affection status/Q2 to marker D8G26 (lod = 1.63).
• Highly significant linkage evidence (lod > 4) using 1% or 2% Q2 cutoffs, requiring screening of over 1,000 families.
• Significant linkage evidence (lod = 3.24) using a 5% Q2 cutoff, requiring screening of approximately 300 families.
• Only suggestive linkage evidence (lod = 1.65) in non-EDSP families.

Conclusions:

• EDSP sampling variants can facilitate convincing replications of genetic findings for complex diseases.
• The effectiveness of EDSP strategy is dependent on the stringency of the trait cutoff used for family selection.
• This approach enables the detection of linkage signals that might otherwise be unobtainable.