Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum
Open accessPublished version of a preprint
Abstract
There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.
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Rare, large-effect variants that increase risk for neurodevelopmental and neuropsychiatric disorders are also associated with deleterious effects on cognition, and ASD is no exception.
“Rare, large-effect variants that increase risk for neurodevelopmental and neuropsychiatric disorders are also associated with deleterious effects on cognition,28, 29, 30 and ASD is no exception.”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [30]
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References 28 · Cited by 110
Research works printed but not linked: 3
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- Authors
- Ganna, A., Satterstrom, F. K., Zekavat, S. M., Das, I., Kurki, M. I., Churchhouse, C., Alfoldi, J., Martin, A. R., Havulinna, A. S., Byrnes, A., Thompson, W. K., Nielsen, P. R., Karczewski, K. J., Saarentaus, E., Rivas, M. A., Gupta, N., Pietiläinen, O., Emdin, C. A., Lescai, F., Bybjerg-Grauholm, J., Flannick, J., Mercader, J. M., Udler, M., Laakso, M., Salomaa, V., Hultman, C., Ripatti, S., Hämäläinen, E., Moilanen, J. S., Körkkö, J., Kuismin, O., Nordentoft, M., Hougaard, D. M., Mors, O., Werge, T., Mortensen, P. B., MacArthur, D., Daly, M. J., Sullivan, P. F., Locke, A. E., Palotie, A., Børglum, A. D., Kathiresan, S., & Neale, B. M.
- Affiliations
- Broad Institute (US)
- Washington University in St. Louis (US)
- University of Helsinki (FI)
- Oslo University Hospital (NO)
- Aarhus University (DK)
- Stanford University (US)
- University of Eastern Finland (FI)
- Finnish Institute for Health and Welfare (FI)
- Karolinska Institutet (SE)
- Oulu University Hospital (FI)
- University of Copenhagen (DK)
- Statens Serum Institut (DK)
- Aarhus University Hospital (DK)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Ganna, Andrea
- Neale, Benjamin M.
- ORCID
- Ganna, Andrea
- Satterstrom, F. Kyle
- Zekavat, Seyedeh M.
- Kurki, Mitja I.
- Martin, Alicia R.
- Havulinna, Aki S.
- Thompson, Wesley K.
- Nielsen, Philip R.
- Karczewski, Konrad J.
- Saarentaus, Elmo
- Rivas, Manuel A.
- Gupta, Namrata
- Pietiläinen, Olli
- Emdin, Connor A.
- Lescai, Francesco
- Flannick, Jason
- Mercader, Josep M.
- Udler, Miriam
- Laakso, Markku
- Salomaa, Veikko
- Hultman, Christina
- Ripatti, Samuli
- Moilanen, Jukka S.
- Kuismin, Outi
- Nordentoft, Merete
- Hougaard, David M.
- Mors, Ole
- Werge, Thomas
- Mortensen, Preben Bo
- MacArthur, Daniel
- Daly, Mark J.
- Sullivan, Patrick F.
- Locke, Adam E.
- Palotie, Aarno
- Børglum, Anders D.
- Kathiresan, Sekar
- Neale, Benjamin M.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 102
- Issue
- 6
- Pages
- 1204-1211
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5992130
- OpenAlex
- W2916821655
- Cited by
- 110
- References
- 28
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 13 · 2022: 18 · 2021: 10 · 2020: 21 · 2019: 20 · 2018: 5 · 2017: 1
- FWCI
- 8.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- UNC Libraries
- WOS
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (1U54DK105566-02)
- Alexander and Margaret Stewart Trust
- National Institute of Mental Health (1R01MH101244-02, RC2 MH089905, 1U01MH105666-01, R01 MH077139)
- Sylvan C. Herman Foundation
- Knut och Alice Wallenbergs Stiftelse (2015.0327)
- Vetenskapsrådet (2016-00250)
- Sydäntutkimussäätiö
- National Human Genome Research Institute (R01 HG006855, U54 HG003067)
- 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 › Genetics and Neurodevelopmental Disorders
- Keywords
- truncating mutations, ultra-rare variants, monogenic disorders, autism spectrum disorder, schizophrenia, bipolar disorder, intellectual disability, attention deficit hyperactivity disorder, quantitative traits, height, educational attainment, hospitalization, pleiotropy, genetic burden, exome sequencing
- MeSH terms
- Ethnicity, Humans, Mutation, Phenotype, Proteins, Open Reading Frames, Genetic Predisposition to Disease, Databases, Genetic, Genome-Wide Association Study
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