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Nat Genet. 2018 Nov;50(11):1600-1607. doi: 10.1038/s41588-018-0231-8. Epub 2018 Oct 8.

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

Gazal S1,2, Loh PR3,4, Finucane HK3,5, Ganna A3,6,7, Schoech A8,3,9, Sunyaev S3,4,10, Price AL11,12,13.

Author information

1
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. sgazal@hsph.harvard.edu.
2
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. sgazal@hsph.harvard.edu.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
5
Schmidt Fellows Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
7
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
8
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
9
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
10
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
11
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. aprice@hsph.harvard.edu.
12
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aprice@hsph.harvard.edu.
13
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. aprice@hsph.harvard.edu.

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 variants (minor allele frequency <0.5%).

PMID:
30297966
PMCID:
PMC6236676
DOI:
10.1038/s41588-018-0231-8
[Indexed for MEDLINE]
Free PMC Article

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