Enriching rare variants using family-specific linkage information.

Area of Science:

• Genetics
• Genomic Medicine

Background:

• Genome-wide association studies (GWAS) identify common variants but fail to explain heritability for complex traits.
• Rare variants, structural variations, and interactions are potential sources of missing heritability.
• Next-generation sequencing enables rare variant discovery in functionally important regions.

Purpose of the Study:

• To investigate the utility of linkage information for selecting families enriched with rare variants.
• To assess the efficiency of targeted family selection for sequencing rare functional variants.

Main Methods:

• Utilized simulated Genetic Analysis Workshop 17 data with phenotypes Q1 and Q2 across 697 subjects in 8 extended pedigrees.
• Selected one pedigree per replicate based on the largest family-specific LOD score.
• Compared carrier probabilities of rare causal alleles in selected versus randomly chosen pedigrees over 200 replications.

Main Results:

• Demonstrated successful enrichment for rare variants, exemplified by the VEGFC gene.
• A rare causal variant (0.0717% MAF) explained 0.1% variance in general population, 7.9% in all pedigrees, and 23.8% in the selected family.
• The carrier family was selected in all 200 replications, confirming effective enrichment.

Conclusions:

• Family-specific linkage information is valuable for selecting pedigrees for sequencing.
• This approach enhances the likelihood of capturing rare functional variants within sequencing samples.
• Improves strategies for dissecting the genetic architecture of complex traits.