The Exome Chip contains non-synonymous, splicing and stop-coding variants that are thought to alter protein expression and function. Our analyses discovered four novel coding variants, indicating potential candidate causal genes at these loci. Our two-stage study design permitted the robust validation of all our novel loci findings, with a large replication sample size from UK Biobank (N = 134 251) to add together to our European discovery data (N = 104 452) for a large combined meta-analysis. However, due to the Exome Chip covering mainly coding regions, we were not able to compare results with all previous GWAS findings. In conclusion, our results taken together with recent studies (12) indicate HR-associated SNVs are mostly common (MAF > 5%) and have relatively small effect sizes. The maximum effect sizes reported thus far are ∼0.70 BPM per allele and MAF of 1% for SNVs at CCDC141 (rs17362588) and GJA1 (rs1015451). An analysis of much larger sample sizes (1M and above) including rare and common SNVs, and samples across different ancestries may provide further information on the contributions of both coding and non-coding variants, and the importance of rare coding variants in HR.
