Are minor alleles more likely to be risk alleles?

Takashi Kido, Weronika Sikora-Wohlfeld, Minae Kawashima, Shinichi Kikuchi, Naoyuki Kamatani, Anil Patwardhan, Richard Chen, Marina Sirota, Keiichi Kodama, Dexter Hadley, Atul J. Butte

Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs < 0.1). Our computer simulations revealed that > 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (< 0.1) were much larger than the expected ratios of GWAS's power imbalance, especially for diseases whose average risk allele frequencies were low, such as myopia, sudden cardiac arrest, and systemic lupus erythematosus. Minor alleles are more likely to be risk alleles in the published GWASs on complex diseases. One reason is that minor alleles are more easily detected as risk alleles in GWASs. Even when correcting for the GWAS's power imbalance, minor alleles are more likely to be risk alleles, especially in some diseases whose average risk allele frequencies are low. These analyses serve as a starting point for future studies on quantifying the degree of negative natural selection in various complex diseases.