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

被引：69

作者：

Ganna, Andrea ^{[1
,2
,3
,4
]}

Satterstrom, F. Kyle ^{[1
,2
,3
]}

Zekavat, Seyedeh M. ^{[2
,5
,6
]}

Das, Indraniel ^{[7
,8
,9
]}

Kurki, Mitja, I ^{[1
,2
,10
]}

Churchhouse, Claire ^{[1
,2
,3
]}

Alfoldi, Jessica ^{[1
,2
]}

Martin, Alicia R. ^{[1
,2
,3
]}

Havulinna, Aki S. ^{[10
,24
,25
]}

Byrnes, Andrea ^{[1
,2
,3
]}

Thompson, Wesley K. ^{[11
,12
,13
,14
]}

Nielsen, Philip R. ^{[13
,15
,16
]}

Karczewski, Konrad J. ^{[1
,2
]}

Saarentaus, Elmo ^{[10
]}

Rivas, Manuel A. ^{[17
]}

Gupta, Namrata ^{[2
]}

Pietilainen, Olli ^{[3
,18
]}

Emdin, Connor A. ^{[2
]}

Lescai, Francesco ^{[13
,19
,20
]}

Bybjerg-Grauholm, Jonas ^{[13
,21
]}

Flannick, Jason ^{[2
,5
,6
]}

Mercader, Josep M. ^{[22
,23
,24
,25
]}

Udler, Miriam ^{[22
,23
,24
,25
]}

Laakso, Markku ^{[26
]}

Salomaa, Veikko ^{[27
]}

Hultman, Christina ^{[4
]}

Ripatti, Samuli ^{[10
,28
,29
]}

Hamalainen, Eija ^{[10
]}

Moilanen, Jukka S. ^{[30
,31
,32
]}

Korkko, Jarmo ^{[30
,31
,32
]}

Kuismin, Outi ^{[30
,31
,32
]}

Nordentoft, Merete ^{[13
,33
]}

Hougaard, David M. ^{[13
,21
]}

Mors, Ole ^{[13
,34
]}

Werge, Thomas ^{[12
,13
,35
]}

Mortensen, Preben Bo ^{[13
,15
,16
,19
]}

MacArthur, Daniel ^{[1
,2
]}

Daly, Mark J. ^{[1
,2
,3
]}

Sullivan, Patrick F. ^{[4
,36
,37
]}

Locke, Adam E. ^{[7
,8
,9
]}

Palotie, Aarno ^{[1
,2
,3
,10
]}

Borglum, Anders D. ^{[13
,19
,20
]}

Kathiresan, Sekar ^{[2
,5
,6
]}

Neale, Benjamin M. ^{[1
,2
,3
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Gen Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Brd Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[3] Brd Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[4] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17176 Stockholm, Sweden

[5] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Gen Med, Boston, MA 02114 USA

[6] Harvard Med Sch, Dept Med, Boston, MA 02114 USA

[7] Washington Univ, McDonnell Genome Inst, Sch Med, St Louis, MO 63108 USA

[8] Univ Michigan, Dept Biostat, Sch Publ Hlth, Ann Arbor, MI 48109 USA

[9] Univ Michigan, Ctr Stat Genet, Sch Publ Hlth, Ann Arbor, MI 48109 USA

[10] Univ Helsinki, Inst Mol Med Finland, FIMM, FIN-00290 Helsinki, Finland

[11] Univ Calif San Diego, Dept Psychiat, San Diego, CA 94143 USA

[12] Inst Biol Psychiat, Mental Hlth Serv Copenhagen, MHC Sct Hans, DK-4000 Roskilde, Denmark

[13] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, Copenhagen, Denmark

[14] Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Norway Div Mental Hlth & Addict, N-0318 Oslo, Norway

[15] Aarhus Univ, Natl Ctr Register Based Res, Sch Business & Social Sci, DK-8210 Aarhus, Denmark

[16] Aarhus Univ, Ctr Integrated Register Based Res, DK-8210 Aarhus, Denmark

[17] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA

[18] Univ Harvard, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[19] Aarhus Univ, iSEQ, Ctr Integrat Sequencing, DK-8210 Aarhus, Denmark

[20] Aarhus Univ, Dept Biomed Human Genet, DK-8210 Aarhus, Denmark

[21] Statens Serum Inst, Ctr Neonatal Screening, Dept Congenital Disorders, DK-2300 Copenhagen, Denmark

[22] Brd Inst Harvard & MIT, Program Metab, Cambridge, MA USA

[23] Brd Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[24] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA

[25] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[26] Univ Eastern Finland, Internal Med, Inst Clin Med, Kuopio 70211, Finland

[27] THL Natl Inst Hlth & Welf, Dept Hlth, Helsinki 00271, Finland

[28] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland

[29] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[30] Univ Oulu, Oulu Univ Hosp, Dept Clin Genet, Oulu 90029, Finland

[31] Univ Oulu, Med Res Ctr Oulu, Oulu 90029, Finland

[32] Univ Oulu, PEDEGO Res Unit, Oulu 90029, Finland

[33] Univ Copenhagen, Mental Hlth Ctr Copenhagen, Mental Hlth Serv Capital Reg Denmark, DK-2100 Copenhagen, Denmark

[34] Aarhus Univ Hosp, Psychosis Res Unit, DK-8240 Risskov, Denmark

[35] Univ Copenhagen, Dept Clin Med, DK-2200 Copenhagen, Denmark

[36] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[37] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 102卷 / 06期

基金：

瑞典研究理事会;

关键词：

ASSOCIATION; VARIANTS; DISORDERS; MUTATIONS; GENES; RISK;

D O I：

10.1016/j.ajhg.2018.05.002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1204 / 1211

页数：8

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