DOI: 10.1101/297572Apr 9, 2018Paper

Low-frequency variant functional architectures reveal strength of negative selection across coding and non-coding annotations

BioRxiv : the Preprint Server for Biology
Steven GazalAlkes L Price


Common variant heritability is known to be concentrated in variants within cell-type-specific non-coding functional annotations, with a limited role for common coding variants. However, little is known about the functional distribution of low-frequency variant heritability. Here, we partitioned the heritability of both low-frequency (0.5% ≤ MAF < 5%) and common (MAF ≥ 5%) variants in 40 UK Biobank traits (average N = 363K) across a broad set of coding and non-coding functional annotations, employing an extension of stratified LD score regression to low-frequency variants that produces robust results in simulations. We determined that non-synonymous coding variants explain 17±1% of low-frequency variant heritability (h2lf) versus only 2.1±0.2% of common variant heritability (h2c), and that regions conserved in primates explain nearly half of h2lf (43±2%). Other annotations previously linked to negative selection, including non-synonymous variants with high PolyPhen-2 scores, non-synonymous variants in genes under strong selection, and low-LD variants, were also significantly more enriched for h2lf as compared to h2c. Cell-type-specific non-coding annotations that were significantly enriched for h2c of corresponding traits tended...Continue Reading

Related Concepts

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.