Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

Publication type

Journal Article

Authors

Publication date

May 4, 2018

Summary:

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.

Published in

bioRxiv

DOI

https://doi.org/10.1101/309070

Subjects

Notes

Open Access

The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-ND 4.0 International license.


Related Publications

#525096

News

Latest findings, new research

Publications search

Search all research by subject and author

Podcasts

Researchers discuss their findings and what they mean for society

Projects

Background and context, methods and data, aims and outputs

Events

Conferences, seminars and workshops

Survey methodology

Specialist research, practice and study

Taking the long view

ISER's annual report

Themes

Key research themes and areas of interest