Rare variants occur at low frequencies (usually defined as a genetic variant for which the rare allele occurs in <1% of a population). The majority of genetic variants analysed in GWAS are common SNPs due to the relative ease in assaying them. Improved imputation methods, and reduced costs of sequencing mean that more genetic associations will be found for rare variants in the future.
Statistical power to detect a genetic association chiefly depends on the sample size and the variance explained by the genetic variant. While the majority of genetic associations with common variants have very small effects, rare variants can only explain sufficiently large variation for detection if they have large effect sizes. The utility of rare variants in MR, therefore, is that they provide an opportunity to evaluate if the causal effect estimate increases linearly with larger intervention sizes.
- Manousaki D, Dudding T, Haworth S et al. Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. Am J Hum Genet 2017;101:227-238.
- Consortium UK, Walter K, Min JL et al. The UK10K project identifies rare variants in health and disease. Nature 2015;526:82-90.