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Cited by 364Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenetic and phenotypic traits in livestock

Functionally informed fine-mapping and polygenic localization of complex trait heritability

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Weissbrod, Omer, Hormozdiari, Farhad, Benner, Christian, Cui, Ran, Ulirsch, Jacob, Gazal, Steven, Schoech, Armin P., van de Geijn, Bryce +6 more·2020·Nature Genetics
DOI 10.1038/s41588-020-00735-5PMC PMC7710571

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Abstract

Fine-mapping aims to identify causal variants impacting complex traits. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy by leveraging functional annotations across the entire genome-not just genome-wide-significant loci-to specify prior probabilities for fine-mapping methods such as SuSiE or FINEMAP. In simulations, PolyFun + SuSiE and PolyFun + FINEMAP were well calibrated and identified >20% more variants with a posterior causal probability >0.95 than identified in their nonfunctionally informed counterparts. In analyses of 49 UK Biobank traits (average n = 318,000), PolyFun + SuSiE identified 3,025 fine-mapped variant-trait pairs with posterior causal probability >0.95, a >32% improvement versus SuSiE. We used posterior mean per-SNP heritabilities from PolyFun + SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 28 (hair color) to 3,400 (height) to 2 million (number of children). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures.

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  • Variant rs11644125 modulates the known motif of the transcription factor SP1.

    “Using in silico mutagenesis of the local region (Methods), we observed that the variant rs11644125 modulates the known motif of the transcription factor SP1 (ref. 24).”

    From Effective gene expression prediction from sequence by integrating long-range interactions (2021) · cites this paper as [24]

    The Results section on fine-mapping of 49 complex traits discusses enrichment of SNPs in functional annotations, but does not address rs11644125 or an SP1 motif. Searches of our copy for rs11644125, the SP1 transcription-factor motif, and in silico mutagenesis found no passage establishing the claimed effect. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Authors
Weissbrod, O., Hormozdiari, F., Benner, C., Cui, R., Ulirsch, J., Gazal, S., Schoech, A. P., van de Geijn, B., Reshef, Y., Márquez-Luna, C., O’Connor, L., Pirinen, M., Finucane, H. K., & Price, A. L.
Affiliations
  • Harvard University (US)
  • University of Helsinki (FI)
  • Broad Institute (US)
Corresponding author
  • Weissbrod, Omer
  • Price, Alkes L.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2020-11-16
Volume
52
Issue
12
Pages
1355-1363
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-020-00735-5
PMC
PMC7710571
OpenAlex
W3102939328
Cited by
364
References
13
Citations by year
2026: 71 · 2025: 84 · 2024: 72 · 2023: 57 · 2022: 46 · 2021: 26 · 2020: 7
FWCI
21.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
Funders
  • Academy of Finland (288509, 312076)
  • Eric and Wendy Schmidt
  • U.S. Department of Health & Human Services | National Institutes of Health (MH107649, MH101244, HG006399, HG009379)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
fine mapping, functional annotation, Susie, causal variant identification, hair color, height, number of children
MeSH terms
Chromosome Mapping, Humans, Phenotype, Genome, Human, Computational Biology, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study

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