Article open access publication

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

American Journal of Human Genetics, Elsevier, ISSN 1537-6605

Volume 102, 6, 2018

DOI:10.1016/j.ajhg.2018.05.002, Dimensions: pub.1104331404, PMC: PMC5992130, PMID: 29861106,



  1. (1) Broad Institute, grid.66859.34
  2. (2) Massachusetts General Hospital, grid.32224.35
  3. (3) Karolinska Institute, grid.4714.6
  4. (4) Harvard University, grid.38142.3c
  5. (5) University of Michigan, grid.214458.e
  6. (6) Washington University in St. Louis, grid.4367.6
  7. (7) University of Helsinki, grid.7737.4
  8. (8) Oslo University Hospital, grid.55325.34
  9. (9) University of California, San Diego, grid.266100.3
  10. (10) Lundbeck Foundation, grid.452548.a
  11. (11) Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde 4000, Denmark
  12. (12) Aarhus University, grid.7048.b, AU
  13. (13) Stanford University, grid.168010.e
  14. (14) State Serum Institute, grid.6203.7
  15. (15) University of Eastern Finland, grid.9668.1
  16. (16) National Institute for Health and Welfare, grid.14758.3f
  17. (17) Wellcome Sanger Institute, grid.10306.34
  18. (18) Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu 90029, Finland
  19. (19) University of Copenhagen, grid.5254.6, KU
  20. (20) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  21. (21) University of North Carolina System, grid.410711.2


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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Research area: Medicine

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Research area: Medicine

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Times Cited: 48

Field Citation Ratio (FCR): 15.7

Relative Citation ratio (RCR): 2.77

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