Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/118253
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dc.contributor.authorNiemi, M.en
dc.contributor.authorMartin, H.en
dc.contributor.authorRice, D.en
dc.contributor.authorGallone, G.en
dc.contributor.authorGordon, S.en
dc.contributor.authorKelemen, M.en
dc.contributor.authorMcAloney, K.en
dc.contributor.authorMcRae, J.en
dc.contributor.authorRadford, E.en
dc.contributor.authorYu, S.en
dc.contributor.authorGecz, J.en
dc.contributor.authorMartin, N.en
dc.contributor.authorWright, C.en
dc.contributor.authorFitzpatrick, D.en
dc.contributor.authorFirth, H.en
dc.contributor.authorHurles, M.en
dc.contributor.authorBarrett, J.en
dc.date.issued2018en
dc.identifier.citationNature, 2018; 562(7726):268-271en
dc.identifier.issn0028-0836en
dc.identifier.issn1476-4687en
dc.identifier.urihttp://hdl.handle.net/2440/118253-
dc.description.abstractThere are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants. However, patients with the same genetic defect can have different clinical presentations, and some individuals who carry known disease-causing variants can appear unaffected. 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.en
dc.description.statementofresponsibilityMari E.K. Niemi, Hilary C. Martin, Daniel L. Rice, Giuseppe Gallone, Scott Gordon, Martin Kelemen, Kerrie McAloney, Jeremy McRae, Elizabeth J. Radford, Sui Yu, Jozef Gecz, Nicholas G. Martin, Caroline F. Wright, David R. Fitzpatrick, Helen V. Firth, Matthew E. Hurles, Jeffrey C. Barretten
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rights© 2018 Springer Nature Limited. All rights reserved.en
dc.subjectHumans; Genetic Predisposition to Disease; Rare Diseases; Birth Weight; Body Height; Case-Control Studies; Cohort Studies; Intelligence; Autistic Disorder; Developmental Disabilities; Schizophrenia; Multifactorial Inheritance; Linkage Disequilibrium; Phenotype; Female; Male; Genetic Variation; Genome-Wide Association Study; Neurodevelopmental Disordersen
dc.titleCommon genetic variants contribute to risk of rare severe neurodevelopmental disordersen
dc.typeJournal articleen
dc.identifier.rmid0030100472en
dc.identifier.doi10.1038/s41586-018-0566-4en
dc.identifier.pubid441108-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS14en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Medicine publications

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