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Abstract
In this paper, we investigated how heritability of low-frequency variants (0.5%= minor allele frequency <5%) is distributed across the genome, and compared it to the distribution of the heritability of common variants We determined that non-synonymous coding variants explain 17 1% of low-frequency variant heritability (hl2f) versus 2.1 0.2% of common variant heritability (hc2). Cell-type-specific non-coding annotations that were significantly enriched for hc2 of corresponding traits were similarly enriched for hl2f for most traits, but more enriched for brain-related annotations and traits. For example, H3K4me3 marks in brain dorsolateral prefrontal cortex explain 57 12% of hl2f versus 12 2% of hc2 for neuroticism. Forward simulations confirmed that low-frequency variant enrichment depends on the mean selection coefficient of causal variants in the annotation, and can be used to predict effect size variance of causal rare variants (minor allele frequency <0.5%).