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Am J Hum Genet DOI:10.1016/j.ajhg.2018.05.002

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

Publication TypeJournal Article
Year of Publication2018
AuthorsGanna, A, F Satterstrom, K, Zekavat, SM, Das, I, Kurki, MI, Churchhouse, C, Alföldi, J, Martin, AR, Havulinna, AS, Byrnes, A, Thompson, WK, Nielsen, PR, Karczewski, KJ, Saarentaus, E, Rivas, MA, Gupta, N, Pietilainen, O, Emdin, CA, Lescai, F, Bybjerg-Grauholm, J, Flannick, J, Mercader, JM, Udler, M, Laakso, M, Salomaa, V, Hultman, C, Ripatti, S, Hämäläinen, E, Moilanen, JS, Körkkö, J, Kuismin, O, Nordentoft, M, Hougaard, DM, Mors, O, Werge, T, Mortensen, PBo, Macarthur, D, Daly, MJ, Sullivan, PF, Locke, AE, Palotie, A, Børglum, AD, Kathiresan, S, Neale, BM
Corporate AuthorsGoT2D/T2D-GENES Consortium, SIGMA Consortium Helmsley IBD Exome Sequencing Project, FinMetSeq Consortium, iPSYCH-Broad Consortium
JournalAm J Hum Genet
Date Published2018 06 07
KeywordsDatabases, Genetic, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mutation, Open Reading Frames, Phenotype, Proteins

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.


Alternate JournalAm J Hum Genet
PubMed ID29861106
PubMed Central IDPMC5992130
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
RC2 MH089905 / MH / NIMH NIH HHS / United States
R01 MH077139 / MH / NIMH NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
K23 DK114551 / DK / NIDDK NIH HHS / United States
U01 MH105666 / MH / NIMH NIH HHS / United States
R01 HG006855 / HG / NHGRI NIH HHS / United States
U54 DK105566 / DK / NIDDK NIH HHS / United States
L30 DK106874 / DK / NIDDK NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
U01 MH109528 / MH / NIMH NIH HHS / United States