Impact of negative selection on the genetic architecture of diseases and complex traits

Abstract: It is widely known that negative selection against genetic
variants that reduce fitness causes them to be enriched for
lower-frequency variants, so that lower-frequency variants have larger
causal effects on diseases and complex traits. Here, we explore two
other ways in which negative selection impacts disease and trait
architectures. First, we show that (conditional on minor allele
frequency) variants with low levels of linkage disequilibrium have
larger causal effects. We show that much of this signal can be
explained by the fact that (conditional on minor allele frequency)
more recent variants have larger causal effects, since negative
selection has had less time to remove them; for example, the youngest
20% of common variants explain 4x more heritability than the oldest
20% of common variants. Second, we show that functional annotations
strongly impacted by negative selection have larger enrichment for
low-frequency variant heritability compared to their enrichment for
common variant heritability, both empirically and in forward
simulations. Cell-type-specific regulatory annotations that are
enriched for common variant heritability tend to be similarly enriched
for low-frequency variant heritability for most annotations and
traits, but more enriched for brain-related annotations and traits.
For example, H3K4me3 marks in brain DPFC explain 57±12% of
low-frequency variant heritability vs. 12±2% of common variant
heritability for neuroticism, implicating the action of negative
selection on low-frequency variants affecting gene regulation in the
brain.