Functional architecture of low-frequency variants highlights strength of negative selection across coding and
Steven Gazal1,2, Po-Ru Loh3,4, Hilary K Finucane3,5
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. sgazal@hsph.harvard.edu.
Nature Genetics
|October 10, 2018
Summary
Low-frequency genetic variants, particularly non-synonymous coding ones, significantly contribute to heritability across many traits. This contrasts with common variants, highlighting distinct functional architectures for different allele frequencies in human genetics.
Area of Science:
- Human Genetics
- Population Genetics
- Genomic Architecture
Background:
- Common variant heritability is largely attributed to non-coding functional elements.
- The functional architecture of low-frequency genetic variants remains largely unexplored.
- Understanding variant architecture is crucial for interpreting genetic association studies.
Purpose of the Study:
- To partition heritability for both low-frequency and common variants across diverse functional annotations.
- To compare the contribution of different variant types (coding vs. non-coding) to heritability at different allele frequencies.
- To investigate the role of cell-type-specific annotations in trait heritability.
Main Methods:
- Heritability partitioning analysis of 40 UK Biobank traits.
- Comparison of heritability explained by common (MAF ≥5%) and low-frequency (0.5% ≤ MAF <5%) variants.
- Analysis across a comprehensive set of functional annotations, including cell-type-specific marks.
- Forward simulations to model variant enrichment and selection effects.
Main Results:
- Non-synonymous coding variants explain a substantial portion (17%) of low-frequency variant heritability, compared to common variants (2.1%).
- Cell-type-specific non-coding annotations enrich heritability for both variant frequencies, with stronger enrichment for brain-related traits and annotations.
- Enrichment of low-frequency variants is dependent on the selection coefficient of causal variants.
Conclusions:
- Low-frequency variants, especially coding non-synonymous ones, play a significant role in trait heritability, distinct from common variants.
- Cell-type-specific regulatory elements are important for both common and low-frequency variant heritability, particularly in the brain.
- The functional architecture of low-frequency variants can be predicted by selection coefficients, offering insights into rare variant effects.
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