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

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GoT2D T2D-GENES Consortium , SIGMA Consortium Helmsley IBD Exom , FinMetSeq Consortium , iPSYCH-Broad Consortium , Ganna , A , Kurki , M , Havulinna , A S , Saarentaus , E , Ripatti , S , Hämäläinen , E , Moilanen , J S , Kuismin , O , Palotie , A & Neale , B M 2018 , ' Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum ' , American Journal of Human Genetics , vol. 102 , no. 6 , pp. 1204-1211 . https://doi.org/10.1016/j.ajhg.2018.05.002

Title: Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum
Author: GoT2D T2D-GENES Consortium; SIGMA Consortium Helmsley IBD Exom; FinMetSeq Consortium; iPSYCH-Broad Consortium; Ganna, Andrea; Kurki, Mitja; Havulinna, Aki S.; Saarentaus, Elmo; Ripatti, Samuli; Hämäläinen, Eija; Moilanen, Jukka S.; Kuismin, Outi; Palotie, Aarno; Neale, Benjamin M.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
Date: 2018-06-07
Language: eng
Number of pages: 8
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
URI: http://hdl.handle.net/10138/302455
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, 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.
Subject: VARIANT ASSOCIATION
GENERAL-POPULATION
DISORDERS
GENOME
MUTATIONS
DISEASE
SAMPLES
AUTISM
RISK
3111 Biomedicine
1184 Genetics, developmental biology, physiology
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