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

Am J Hum Genet. 2018 Jun 7;102(6):1204-1211. doi: 10.1016/j.ajhg.2018.05.002. Epub 2018 May 31.


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.

Keywords: burden analysis; constraint genes; exome sequencing; phewas; rare variants; selection; ultra-rare variants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Databases, Genetic
  • Ethnicity / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Mutation / genetics*
  • Open Reading Frames / genetics*
  • Phenotype
  • Proteins / genetics


  • Proteins