Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Genome-wide association studies (GWAS) have identified variants linked to platelet function, but explain little variance.
• Rare coding variants, potentially impacting protein function, are difficult to detect with GWAS.
• Understanding genetic contributions to platelet function is crucial for diagnosing and treating bleeding disorders.

Purpose of the Study:

• To identify low-frequency or rare genetic variants associated with platelet function using exome genotyping data.
• To investigate the role of rare variants in adenosine diphosphate (ADP)-, epinephrine-, and collagen-induced platelet aggregation.
• To leverage gene-based and single nucleotide variant (SNV) association methods for novel discoveries.

Main Methods:

• Utilized genotype data from the Illumina HumanExome Bead Chip across three family-based European cohorts (~4,000 subjects) for discovery.
• Employed optical aggregometry in platelet-rich plasma stimulated by ADP, epinephrine, and collagen.
• Performed meta-analyses using gene-based and SNV association methods, with replication in independent European and African American cohorts.

Main Results:

• A significant association (P = 7.13 × 10^-7) was found between rare variants in ANKRD26 and ADP-induced platelet aggregation via gene-based meta-analysis.
• Replication in European cohorts confirmed the association of ANKRD26 SNV rs191015656, predicted to alter protein function, with increased aggregation in heterozygotes (~20-50%).
• Novel associations with ADP-induced platelet aggregation were observed for ABCG1 and HCP5, with HCP5 replication and evidence suggesting a role in platelet biology.

Conclusions:

• This study is the first to use gene-based association methods with SNV array genotypes to identify rare variants influencing platelet function.
• Rare variants in ANKRD26 significantly impact ADP-induced platelet aggregation, suggesting a role in platelet disorders.
• Further research is needed to elucidate the molecular mechanisms and pathophysiological relevance of these genetic associations, particularly for ANKRD26, ABCG1, and HCP5.