Functional architecture of low-frequency variants highlights strength of negative selection across coding and non-coding annotations

Nature Genetics
Steven GazalAlkes L Price

Abstract

Common variant heritability has been widely reported to be concentrated in variants within cell-type-specific non-coding functional annotations, but little is known about low-frequency variant functional architectures. We partitioned the heritability of both low-frequency (0.5%≤ minor allele frequency <5%) and common (minor allele frequency ≥5%) variants in 40 UK Biobank traits across a broad set of functional annotations. We determined that non-synonymous coding variants explain 17 ± 1% of low-frequency variant heritability ([Formula: see text]) versus 2.1 ± 0.2% of common variant heritability ([Formula: see text]). Cell-type-specific non-coding annotations that were significantly enriched for [Formula: see text] of corresponding traits were similarly enriched for [Formula: see text] 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 [Formula: see text] versus 12 ± 2% of [Formula: see text] 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 v...Continue Reading

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Citations

Jul 10, 2019·Nature Genetics·Steven GazalAlkes L Price
Feb 1, 2020·Briefings in Bioinformatics·Wei-Yang BaiHou-Feng Zheng
May 28, 2019·Genetics·Eugenio López-Cortegano, Armando Caballero
Oct 9, 2019·Human Molecular Genetics·Bryce van de GeijnAlkes L Price
Sep 8, 2019·Nature Communications·Farhad HormozdiariAlkes L Price
Sep 16, 2020·Genetic Epidemiology·Georg HahnUNKNOWN NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Aug 13, 2020·Nature Communications·Ali PazokitoroudiSriram Sankararaman
Jul 20, 2020·Human Genetics·Atsuko OkazakiJurg Ott
Jul 31, 2020·Nature·Fabian GrubertMichael Snyder
Sep 22, 2020·ELife·Pascal N TimshelTune H Pers
Sep 19, 2020·Nature Communications·Kushal K DeyAlkes L Price
Jun 6, 2019·Human Genetics·Emmanuelle Génin
Jul 31, 2020·Nature·Wouter MeulemanJohn Stamatoyannopoulos
Sep 9, 2020·Annual Review of Genetics·Christopher M Jakobson, Daniel F Jarosz
Mar 11, 2021·American Journal of Human Genetics·Arun Durvasula, Kirk E Lohmueller
Apr 10, 2021·Proceedings of the National Academy of Sciences of the United States of America·Brooke SheppardAndy Dahl
Apr 4, 2021·American Journal of Human Genetics·Ali PazokitoroudiSriram Sankararaman
Jul 1, 2019·Genetics·Eugenio López-Cortegano, Armando Caballero

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Methods Mentioned

BETA
chip
acetylation

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