An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people
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A Deep Look Into Our Genes: Recent debates have focused on the degree of genetic variation and its impact upon health at the genomic level in humans (see the Perspective by Casals and Bertranpetit ). Tennessen et al. (p. 64 , published online 17 May), looking at all of the protein-coding genes in the human genome, and Nelson et al. (p. 100 , published online 17 May), looking at genes that encode drug targets, address this question through deep sequencing efforts on samples from multiple individuals. The findings suggest that most human variation is rare, not shared between populations, and that rare variants are likely to play a role in human health.
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Common genetic variants generally have small effects on disease risk (OR <1.15), while rare variants typically have larger effect sizes (>2.0), are more likely deleterious, and tend to be removed by natural selection.
“Given what we know now, common variants generally have small effects on disease risk (OR <1.15), and rare variants typically have larger effect sizes (>2.0), are more likely to be deleterious, and tend to be removed by natural selection (Fu et al., 2013; Nelson et al., 2012; Zeng et al., 2018).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Nelson et al., 2012
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- Authors
- Nelson, M. R., Wegmann, D., Ehm, M. G., Kessner, D., St. Jean, P., Verzilli, C., Shen, J., Tang, Z., Bacanu, S.-A., Fraser, D., Warren, L., Aponte, J., Zawistowski, M., Liu, X., Zhang, H., Zhang, Y., Li, J., Li, Y., Li, L., Woollard, P., Topp, S., Hall, M. D., Nangle, K., Wang, J., Abecasis, G., Cardon, L. R., Zöllner, S., Whittaker, J. C., Chissoe, S. L., Novembre, J., & Mooser, V.
- Affiliations
- GlaxoSmithKline (United States) (US)
- University of California, Los Angeles (US)
- Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA.
- GlaxoSmithKline (United Kingdom) (GB)
- Department of Genetics and Biostatistics, University of North Carolina–Chapel Hill, Chapel Hill, NC 27599, USA.
- University of Michigan (US)
- BGI Group (China) (CN)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Nelson, Matthew R.
- Wegmann, Daniel
- Ehm, Margaret G.
- Shen, Judong
- Bacanu, Silviu-Alin
- Fraser, Dana
- Warren, Liling
- Zawistowski, Matthew
- Liu, Xiao
- Zhang, Hao
- Zhang, Yong
- Li, Jun
- Li, Yun
- Li, Li
- Woollard, Peter
- Topp, Simon
- Hall, Matthew D.
- Wang, Jun
- Abecasis, Gonçalo
- Zöllner, Sebastian
- Whittaker, John C.
- Novembre, John
- Mooser, Vincent
- Venue
- Science
- Published
- 2012-07-06
- Volume
- 337
- Issue
- 6090
- Pages
- 100-104
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4319976
- OpenAlex
- W1982516282
- Cited by
- 647
- References
- 83
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 11 · 2023: 11 · 2022: 20 · 2021: 23 · 2020: 29 · 2019: 31 · 2018: 42 · 2017: 44 · 2016: 80 · 2015: 70 · 2014: 97 · 2013: 122 · 2012: 46
- FWCI
- 64.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Human Genome Research Institute (U01HG006513, T32HG002536)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- rare variants, drug target genes, population growth, purifying selection, deleterious mutations, mutation rate, human genetic variation
- MeSH terms
- Black or African American, Disease, Gene Frequency, Geography, Humans, Pharmacogenetics, Phenotype, Population Growth, Selection, Genetic, Genetic Variation, Genome, Human, Sample Size, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, White People, Asian People, Genetic Association Studies, Molecular Targeted Therapy, High-Throughput Nucleotide Sequencing, Mutation Rate
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