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Nat Genet DOI:10.1038/s41588-018-0231-8

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

Publication TypeJournal Article
Year of Publication2018
AuthorsGazal, S, Loh, P-R, Finucane, HK, Ganna, A, Schoech, A, Sunyaev, S, Price, AL
JournalNat Genet
Date Published2018 Nov
KeywordsAlleles, Biological Specimen Banks, Gene Frequency, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Molecular Sequence Annotation, Open Reading Frames, Polymorphism, Single Nucleotide, Selection, Genetic, United Kingdom, Whites

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 variants (minor allele frequency <0.5%).


Alternate JournalNat Genet
PubMed ID30297966
PubMed Central IDPMC6236676
Grant ListMC_QA137853 / MRC_ / Medical Research Council / United Kingdom
K99 HG010160 / HG / NHGRI NIH HHS / United States
U01 HG009379 / HG / NHGRI NIH HHS / United States
R01 MH107649 / MH / NIMH NIH HHS / United States
R01 MH109978 / MH / NIMH NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
R01 MH101244 / MH / NIMH NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States