Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Andrea Ganna; F. Kyle Satterstrom; Seyedeh Maryam Zekavat; Indraniel Das; Mitja Kurki; Claire Churchhouse; Jessica Alföldi; Alicia R. Martin; Aki Samuli Havulinna; Andrea Byrnes; Wesley Kurt Thompson; Philip Rising Nielsen; Konrad J. Karczewski; Elmo Saarentaus; Manuel A. Rivas; Namrata Gupta; Olli P. H. Pietiläinen; Connor A. Emdin; Francesco Lescai; Jonas Bybjerg‐Grauholm; Jason A. Flannick; Josep Maria Mercader; Miriam S. Udler; Markku Laakso; Veikko V Salomaa; Christina M. Hultman; Samuli Ripatti; Eija Hämäläinen; Jukka S. Moilanen; Jarmo Körkkö

doi:10.1016/j.ajhg.2018.05.002

GeneticsThe American Journal of Human GeneticsMay 31, 2018

Peer-reviewed journal article

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

Andrea Ganna iD, F. Kyle Satterstrom iD, Seyedeh Maryam Zekavat iD, Indraniel Das, Mitja Kurki iD, Claire Churchhouse, Jessica Alföldi iD, Alicia R. Martin iD, Aki Samuli Havulinna iD, Andrea Byrnes, Wesley Kurt Thompson iD, Philip Rising Nielsen iD, Konrad J. Karczewski iD, Elmo Saarentaus iD, Manuel A. Rivas iD, Namrata Gupta iD, Olli P. H. Pietiläinen iD, Connor A. Emdin iD, Francesco Lescai iD, Jonas Bybjerg‐Grauholm iD, Jason A. Flannick iD, Josep Maria Mercader iD, Miriam S. Udler iD, Markku Laakso iD, Veikko V Salomaa iD, , Benjamin M. Neale iD

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, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. 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.\n\nMain abbreviations

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