Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

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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Affiliated Institutions

• Massachusetts General Hospital US
• Oslo University Hospital
• Harvard University US
• Statens Serum Institut DK
• Oulu University Hospital FI
• Institute for Molecular Medicine Finland FI
• James S. McDonnell Foundation US
• Stanford University US
• University of Eastern Finland FI
• Lundbeck Foundation DK
• Aarhus University DK
• University of Oulu FI
• University of California, San Diego US
• Finnish Institute for Health and Welfare FI
• Aarhus University Hospital DK
• University of Michigan US
• Mental Health Services DK
• Capital Region of Denmark DK
• University of Helsinki FI
• Wellcome Sanger Institute GB
• Broad Institute US
• University of North Carolina at Chapel Hill US
• University of Copenhagen DK
• Karolinska Institutet SE

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