PT  - JOURNAL ARTICLE
AU  - Andrea Ganna
AU  - F. Kyle Satterstrom
AU  - Seyedeh M Zekavat
AU  - Indraniel Das
AU  - Mitja I. Kurki
AU  - Claire Churchhouse
AU  - Jessica Alfoldi
AU  - Alicia R. Martin
AU  - Aki S. Havulinna
AU  - Andrea Byrnes
AU  - Wesley K. Thompson
AU  - Philip R. Nielsen
AU  - Konrad J. Karczewski
AU  - Elmo Saarentaus
AU  - Manuel A. Rivas
AU  - Namrata Gupta
AU  - Olli Pietiläinen
AU  - Connor A Emdin
AU  - Francesco Lescai
AU  - Jonas Bybjerg-Grauholm
AU  - Jason Flannick
AU  - on behalf of GoT2D/T2D-GENES consortium
AU  - Josep Mercader
AU  - Miriam Udlerg
AU  - on behalf of SIGMA consortium
AU  - Helmsley IBD Exome Sequencing Project
AU  - FinMetSeq Consortium
AU  - iPSYCH-Broad Consortium
AU  - Markku Laakso
AU  - Veikko Salomaa
AU  - Christina Hultman
AU  - Samuli Ripatti
AU  - Eija Hämäläinen
AU  - Jukka S Moilanen
AU  - Jarmo Körkkö
AU  - Outi Kuismin
AU  - Merete Nordentoft
AU  - David M. Hougaard
AU  - Ole Mors
AU  - Thomas Werge
AU  - Preben Bo Mortensen
AU  - Daniel MacArthur
AU  - Mark J. Daly
AU  - Patrick F. Sullivan
AU  - Adam E. Locke
AU  - Aarno Palotie
AU  - Anders D. Børglum
AU  - Sekar Kathiresan
AU  - Benjamin M. Neale
TI  - Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum
AID  - 10.1101/148247
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 148247
4099  - http://biorxiv.org/content/early/2017/06/09/148247.short
4100  - http://biorxiv.org/content/early/2017/06/09/148247.full
AB  - Protein truncating variants (PTVs) are likely to modify gene function and have been linked to hundreds of Mendelian disorders1,2. However, the impact of PTVs on complex traits has been limited by the available sample size of whole-exome sequencing studies (WES) 3. Here we assemble WES data from 100,304 individuals to quantify the impact of rare PTVs on 13 quantitative traits and 10 diseases. We focus on those PTVs that occur in PTV-intolerant (PI) genes, as these are more likely to be pathogenic. Carriers of at least one PI-PTV were found to have an increased risk of autism, schizophrenia, bipolar disorder, intellectual disability and ADHD (P-value (p) range: 5×10−3−9×10−12). In controls, without these disorders, we found that this burden associated with increased risk of mental, behavioral and neurodevelopmental disorders as captured by electronic health record information. Furthermore, carriers of PI-PTVs tended to be shorter (p=2×10−5), have fewer years of education (p=2×10−4) and be younger (p=2×10−7); the latter observation possibly reflecting reduced survival or study participation. While other gene-sets derived from in vivo experiments did not show any associations with PTV-burden, gene sets implicated in GWAS of cardiovascular-related traits and inflammatory bowel disease showed a significant PTV-burden with corresponding traits, mainly driven by established genes involved in familial forms of these disorders. We leveraged population health registries from 14,117 individuals to study the phenome-wide impact of PIPTVs and identified an increase in the number of hospital visits among PI-PTV carriers. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.Collaborators Helmsley IBD Exome Sequencing Project: Dermot McGovern, Judy H Cho, Ann Pulver, Vincent Plagnol, Tony Segal, Gil Atzmon, Dan Turner, Ben Glaser, Inga Peter, Ramnik Xavier, Harry Sokol, Rinse Weersma, Andre Franke, John Rioux, Tariq Ahmad, Martti Färkkilä, Kimmo Kontula.FinMetSeq Consortium: Haley J Abel, Michael Boehnke, Lei Chen, Charleston WK Chiang, Colby C Chiang, Susan K Dutcher, Nelson B Freimer, Robert S Fulton, Liron Ganel, Ira M Hall, Anne U Jackson, Krishna L Kanchi, Chul Joo Kang, Daniel C Koboldt, Hannele Laivuori, David E Larson, Karyn Meltz Steinberg, Joanne Nelson, Thomas J Nicholas, Arto Pietilä, Matti Pirinen, Vasily Ramensky, Debashree Ray, Chiara Sabatti, Laura J Scott, Susan Service, Laurel Stell, Nathan O Stitziel, Heather M Stringham, Ryan Welch, Richard K Wilson, Pranav Yajnik.iPSYCH-Broad Consortium: Marianne G Pedersen, Marie Bækvad-Hansen, Christine S Hansen.