HOPS: a quantitative score reveals pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases
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Abstract
Horizontal pleiotropy, where one variant has independent effects on multiple traits, is important for our understanding of the genetic architecture of human phenotypes. We develop a method to quantify horizontal pleiotropy using genome-wide association summary statistics and apply it to 372 heritable phenotypes measured in 361,194 UK Biobank individuals. Horizontal pleiotropy is pervasive throughout the human genome, prominent among highly polygenic phenotypes, and enriched in active regulatory regions. Our results highlight the central role horizontal pleiotropy plays in the genetic architecture of human phenotypes. The HOrizontal Pleiotropy Score (HOPS) method is available on Github at https://github.com/rondolab/HOPS .
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Pleiotropy is pervasive, as uncovered through genome-wide association studies.
“However, the topic has received renewed attention, given the pervasiveness of pleiotropy that has been uncovered through genome-wide association studies (GWAS) [8–10].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [9]
At some pleiotropic loci, there is no shared causal SNP; instead, different SNPs are causal for different traits.
“However, recent studies have shown that at some pleiotropic loci there is no shared causal SNP, but instead different SNPs are causal for the different traits. These loci are associated with multiple traits but there is no shared causal genetic variant behind the associations [9, 15].”
From Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits (2021) · cites this paper as [9]
The Results (‘Defining pleiotropy’; page unavailable) define pleiotropy as one variant associated with multiple traits. The Methods (‘Genome-wide significant pleiotropy loci’; page unavailable) describe clustering linked variants, but neither passage establishes loci where different traits have different causal SNPs and no shared causal variant. Searches for distinct causal variants, colocalization, and linkage disequilibrium did not find that claim in our copy. (LLM, conf=0.73)
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- Authors
- Jordan, D. M., Verbanck, M., & Do, R.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Université Paris Cité (FR)
- Corresponding author
- Do, Ron
- Venue
- Genome Biology
- Published
- 2019-10-25
- Volume
- 20
- Issue
- 1
- Pages
- 222-222
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC6815001
- OpenAlex
- W2981563631
- Cited by
- 73
- References
- 75
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 14 · 2023: 4 · 2022: 7 · 2021: 15 · 2020: 14 · 2019: 4
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (R35GM124836)
- National Heart, Lung, and Blood Institute (R01HL139865, T32HL00782)
- American Heart Association (15CVGPSD27130014)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- horizontal pleiotropy, polygenic traits, genetic architecture, regulatory elements, genetic variants, UK Biobank, genome-wide association summary statistics
- MeSH terms
- Humans, Genetic Variation, Genome, Human, Multifactorial Inheritance, Genomics, Genome-Wide Association Study, Genetic Pleiotropy
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