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Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

By Mari 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 Barrett

Posted 04 May 2018
bioRxiv DOI: 10.1101/309070 (published DOI: 10.1038/s41586-018-0566-4)

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant. However, patients with the same genetic defect can have different clinical presentation, and some individuals carrying known disease-causing variants can appear unaffected. What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, 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, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.

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