Cited by 340Genetic Associations and EpidemiologyGenomics and Rare DiseasesGenetics and Neurodevelopmental Disorders

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Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

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Niemi, Mari E. K., Martin, Hilary C., Rice, Daniel L., Gallone, Giuseppe, Gordon, Scott, Kelemen, Martin, McAloney, Kerrie, McRae, Jeremy, Radford, Elizabeth J., Yu, Sui, Gecz, Jozef, Martin, Nicholas G., Wright, Caroline F., Fitzpatrick, David R., Firth, Helen V., Hurles, Matthew E., Barrett, Jeffrey C.·2018·Nature

DOI 10.1038/s41586-018-0566-4PMC PMC6726472

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Abstract

There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants 1. However, patients with the same genetic defect can have different clinical presentations 2-4, and some individuals who carry known disease-causing variants can appear unaffected 5. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.

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Authors: Niemi, M. E. K., Martin, H. C., Rice, D. L., Gallone, G., Gordon, S., Kelemen, M., McAloney, K., McRae, J., Radford, E. J., Yu, S., Gecz, J., Martin, N. G., Wright, C. F., Fitzpatrick, D. R., Firth, H. V., Hurles, M. E., & Barrett, J. C.
Affiliations: Wellcome Sanger Institute (GB)
QIMR Berghofer Medical Research Institute (AU)
University of Cambridge (GB)
South Australia Pathology (AU)
University of Exeter (GB)
Western General Hospital (GB)
Cambridge University Hospitals NHS Foundation Trust (GB)
Corresponding author: Barrett, Jeffrey C.
ORCID: Niemi, Mari E. K.
Martin, Hilary C.
Rice, Daniel L.
Gordon, Scott
Kelemen, Martin
McAloney, Kerrie
McRae, Jeremy
Radford, Elizabeth J.
Yu, Sui
Martin, Nicholas G.
Wright, Caroline F.
Fitzpatrick, David R.
Firth, Helen V.
Hurles, Matthew E.
Barrett, Jeffrey C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-09-26
Volume: 562
Issue: 7726
Pages: 268-271
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0566-4
PMC: PMC6726472
OpenAlex: W2952988698
Cited by: 340
References: 46
Citations by year: 2026: 20 · 2025: 45 · 2024: 39 · 2023: 41 · 2022: 54 · 2021: 52 · 2020: 41 · 2019: 41 · 2018: 7
FWCI: 21.62
Type: journal article
Language: en
Open access: green
doi.org
Licence: cc-by-nd
www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Open Research Exeter (University of Exeter) (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Figshare (submittedVersion)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
Apollo
Funders: University of Essex (ES/M008592/1)
Wellcome Trust (HICF-1009-003, 091986, GEN/284/12, WT 098051, 10/H0305/83, 213422/Z/18/Z, 098051)
Understanding Society
National Institute for Health and Care Research (10/H0305/83, ACF-2015-14-007, HICF-1009-003, WT098051)
Medical Research Council (MR/N01104X/1, MR/N01104X/2, WT098051, MC_UU_00007/3, Grant Number: MR/N01104X/1)
Economic and Social Research Council (MR/N01104X/1, ES/M008592/1, ES/S008349/1)
National Health and Medical Research Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: neurodevelopmental disorders, common genetic variants, monogenic disorders, global developmental delay, autism spectrum disorder, genetic burden, educational attainment, intelligence, schizophrenia risk, phenotypic expression, clinical heterogeneity, intracranial volume, birth weight, height
MeSH terms: Autistic Disorder, Birth Weight, Body Height, Developmental Disabilities, Female, Humans, Intelligence, Male, Phenotype, Schizophrenia, Genetic Variation, Cohort Studies, Linkage Disequilibrium, Case-Control Studies, Genetic Predisposition to Disease, Multifactorial Inheritance, Rare Diseases, Genome-Wide Association Study, Neurodevelopmental Disorders

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