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

Andrea Ganna; F. Kyle Satterstrom; Seyedeh M. Zekavat; Indraniel Das; Mitja I. Kurki; Claire Churchhouse; Jessica Alfoldi; Alicia R. Martin; Aki S. Havulinna; Andrea Byrnes; Wesley K. Thompson; Philip R. Nielsen; Konrad J. Karczewski; Elmo Saarentaus; Manuel A. Rivas; Namrata Gupta; Olli Pietiläinen; Connor A. Emdin; Francesco Lescai; Jonas Bybjerg-Grauholm; Jason Flannick; GoT2D/T2D-GENES Consortium; Josep M. Mercader; Miriam Udler; SIGMA Consortium Helmsley IBD Exome Sequencing Project; FinMetSeq Consortium; iPSYCH-Broad Consortium; Markku Laakso; Veikko Salomaa; Christina Hultman; Samuli Ripatti; Eija Hämäläinen; Jukka S. Moilanen; Jarmo Körkkö; Outi Kuismin; Merete Nordentoft; David M. Hougaard; Ole Mors; Thomas Werge; Preben Bo Mortensen; Daniel MacArthur; Mark J. Daly; Patrick F. Sullivan; Adam E. Locke; Aarno Palotie; Anders D. Børglum; Sekar Kathiresan; Benjamin M. Neale

doi:10.1016/j.ajhg.2018.05.002

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

Andrea Ganna^*, F. Kyle Satterstrom, Seyedeh M. Zekavat, Indraniel Das, Mitja I. Kurki, Claire Churchhouse, Jessica Alfoldi, Alicia R. Martin, Aki S. Havulinna, Andrea Byrnes, Wesley K. Thompson, Philip R. Nielsen, Konrad J. Karczewski, Elmo Saarentaus, Manuel A. Rivas, Namrata Gupta, Olli Pietiläinen, Connor A. Emdin, Francesco Lescai, Jonas Bybjerg-GrauholmJason Flannick, GoT2D/T2D-GENES Consortium, Josep M. Mercader, Miriam Udler, SIGMA Consortium Helmsley IBD Exome Sequencing Project, FinMetSeq Consortium, iPSYCH-Broad Consortium, Markku Laakso, Veikko Salomaa, Christina Hultman, Samuli Ripatti, Eija Hämäläinen, Jukka S. Moilanen, Jarmo Körkkö, Outi Kuismin, Merete Nordentoft, David M. Hougaard, Ole Mors, Thomas Werge, Preben Bo Mortensen, Daniel MacArthur, Mark J. Daly, Patrick F. Sullivan, Adam E. Locke, Aarno Palotie, Anders D. Børglum, Sekar Kathiresan, Benjamin M. Neale

^*Corresponding author for this work

Department of Clinical Medicine

36 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Human Genetics
Volume	102
Issue number	6
Pages (from-to)	1204-1211
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2018.05.002
Publication status	Published - 2018

Keywords

burden analysis
constraint genes
exome sequencing
phewas
rare variants
selection
ultra-rare variants

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10.1016/j.ajhg.2018.05.002

http://europepmc.org/articles/pmc5992130?pdf=render

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Ganna, A., Satterstrom, F. K., Zekavat, S. M., Das, I., Kurki, M. I., Churchhouse, C., Alfoldi, J., Martin, A. R., Havulinna, A. S., Byrnes, A., Thompson, W. K., Nielsen, P. R., Karczewski, K. J., Saarentaus, E., Rivas, M. A., Gupta, N., Pietiläinen, O., Emdin, C. A., Lescai, F., ... Neale, B. M. (2018). Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum. American Journal of Human Genetics, 102(6), 1204-1211. https://doi.org/10.1016/j.ajhg.2018.05.002

Ganna, A, Satterstrom, FK, Zekavat, SM, Das, I, Kurki, MI, Churchhouse, C, Alfoldi, J, Martin, AR, Havulinna, AS, Byrnes, A, Thompson, WK, Nielsen, PR, Karczewski, KJ, Saarentaus, E, Rivas, MA, Gupta, N, Pietiläinen, O, Emdin, CA, Lescai, F, Bybjerg-Grauholm, J, Flannick, J, GoT2D/T2D-GENES Consortium, Mercader, JM, Udler, M, SIGMA Consortium Helmsley IBD Exome Sequencing Project, FinMetSeq Consortium, iPSYCH-Broad Consortium, 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, PB, MacArthur, D, Daly, MJ, Sullivan, PF, Locke, AE, Palotie, A, Børglum, AD, Kathiresan, S & Neale, BM 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

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title = "Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum",

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.",

keywords = "burden analysis, constraint genes, exome sequencing, phewas, rare variants, selection, ultra-rare variants",

author = "Andrea Ganna and Satterstrom, {F. Kyle} and Zekavat, {Seyedeh M.} and Indraniel Das and Kurki, {Mitja I.} and Claire Churchhouse and Jessica Alfoldi and Martin, {Alicia R.} and Havulinna, {Aki S.} and Andrea Byrnes and Thompson, {Wesley K.} and Nielsen, {Philip R.} and Karczewski, {Konrad J.} and Elmo Saarentaus and Rivas, {Manuel A.} and Namrata Gupta and Olli Pietil{\"a}inen and Emdin, {Connor A.} and Francesco Lescai and Jonas Bybjerg-Grauholm and Jason Flannick and {GoT2D/T2D-GENES Consortium} and Mercader, {Josep M.} and Miriam Udler and {SIGMA Consortium Helmsley IBD Exome Sequencing Project} and {FinMetSeq Consortium} and {iPSYCH-Broad Consortium} and Markku Laakso and Veikko Salomaa and Christina Hultman and Samuli Ripatti and Eija H{\"a}m{\"a}l{\"a}inen and Moilanen, {Jukka S.} and Jarmo K{\"o}rkk{\"o} and Outi Kuismin and Merete Nordentoft and Hougaard, {David M.} and Ole Mors and Thomas Werge and Mortensen, {Preben Bo} and Daniel MacArthur and Daly, {Mark J.} and Sullivan, {Patrick F.} and Locke, {Adam E.} and Aarno Palotie and B{\o}rglum, {Anders D.} and Sekar Kathiresan and Neale, {Benjamin M.}",

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doi = "10.1016/j.ajhg.2018.05.002",

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AU - Ganna, Andrea

AU - Satterstrom, F. Kyle

AU - Zekavat, Seyedeh M.

AU - Das, Indraniel

AU - Kurki, Mitja I.

AU - Churchhouse, Claire

AU - Alfoldi, Jessica

AU - Martin, Alicia R.

AU - Havulinna, Aki S.

AU - Byrnes, Andrea

AU - Thompson, Wesley K.

AU - Nielsen, Philip R.

AU - Karczewski, Konrad J.

AU - Saarentaus, Elmo

AU - Rivas, Manuel A.

AU - Gupta, Namrata

AU - Pietiläinen, Olli

AU - Emdin, Connor A.

AU - Lescai, Francesco

AU - Bybjerg-Grauholm, Jonas

AU - Flannick, Jason

AU - GoT2D/T2D-GENES Consortium

AU - Mercader, Josep M.

AU - Udler, Miriam

AU - SIGMA Consortium Helmsley IBD Exome Sequencing Project

AU - FinMetSeq Consortium

AU - iPSYCH-Broad Consortium

AU - Laakso, Markku

AU - Salomaa, Veikko

AU - Hultman, Christina

AU - Ripatti, Samuli

AU - Hämäläinen, Eija

AU - Moilanen, Jukka S.

AU - Körkkö, Jarmo

AU - Kuismin, Outi

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Mors, Ole

AU - Werge, Thomas

AU - Mortensen, Preben Bo

AU - MacArthur, Daniel

AU - Daly, Mark J.

AU - Sullivan, Patrick F.

AU - Locke, Adam E.

AU - Palotie, Aarno

AU - Børglum, Anders D.

AU - Kathiresan, Sekar

AU - Neale, Benjamin M.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - burden analysis

KW - constraint genes

KW - exome sequencing

KW - phewas

KW - rare variants

KW - selection

KW - ultra-rare variants

U2 - 10.1016/j.ajhg.2018.05.002

DO - 10.1016/j.ajhg.2018.05.002

M3 - Journal article

C2 - 29861106

AN - SCOPUS:85047311473

SN - 0002-9297

VL - 102

SP - 1204

EP - 1211

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

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

Abstract

Keywords

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