Per-allele disease and complex trait effect sizes are predominantly African MAF-dependent in European populations

Understanding genetic architectures of disease is fundamental to partitioning heritability, polygenic risk prediction, and statistical fine-mapping. Genetic architectures of disease in European populations have been shown to depend on European minor allele frequency (MAF): SNPs with lower MAF have larger per-allele effects, due to the action of negative selection. However, we hypothesized that African MAF (defined using African-ancestry segments in African Americans), which is not distorted by the out-of-Africa bottleneck, might better predict per-allele effect sizes of common genetic variation in European populations; we note that common variants explaining most disease heritability are typically much older than the split between African and non-African populations. To demonstrate this, we first analyze the proportion of non-synonymous SNPs, which are strongly impacted by negative selection. The proportion of non-synonymous SNPs is much better predicted by African MAF than European MAF; a mixture of African MAF with weight w=0.95 (95% CI: (0.93, 0.96)) and European MAF with weight (1−w) is a more powerful predictor than either European MAF (P