A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

被引：103

作者：

Antaki, Danny ^{[1
,2
,3
,4
,5
,6
]}

Guevara, James ^{[2
,3
]}

Maihofer, Adam X. ^{[3
]}

Klein, Marieke ^{[2
,3
]}

Gujral, Madhusudan ^{[2
,3
]}

Grove, Jakob ^{[7
,8
,9
,10
,11
]}

Carey, Caitlin E. ^{[12
]}

Hong, Oanh ^{[2
,3
]}

Arranz, Maria J. ^{[13
]}

Hervas, Amaia ^{[14
]}

Corsello, Christina ^{[15
]}

Vaux, Keith K. ^{[16
]}

Muotri, Alysson R. ^{[4
,5
,17
]}

Iakoucheva, Lilia M. ^{[3
,5
]}

Courchesne, Eric ^{[6
,18
,19
]}

Pierce, Karen ^{[6
,18
,19
]}

Gleeson, Joseph G. ^{[5
,6
]}

Robinson, Elise B. ^{[12
]}

Nievergelt, Caroline M. ^{[3
]}

Sebat, Jonathan ^{[2
,3
,4
,5
]}

机构：

[1] Univ Calif San Diego, Biomed Sci Grad Program, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Beyster Ctr Psychiat Genom, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[7] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[8] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark

[9] ISEQ, Ctr Genom & Personalized Med, Aarhus, Denmark

[10] ISEQ, Ctr Integrat Sequencing, Aarhus, Denmark

[11] Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark

[12] Broad Inst MIT & Harvard, Harvard TH Chan Sch Publ Hlth, Cambridge, MA 02142 USA

[13] Fundacio Docencia & Recerca Mutua, Res Lab Unit, Terrassa, Spain

[14] Hosp Univ Mutua Terrassa, Child & Adolescent Mental Hlth Unit, Barcelona, Spain

[15] Univ N Carolina, TEACCH Autism Program, Chapel Hill, NC 27515 USA

[16] Human Longev Inc, San Diego, CA USA

[17] Univ Calif San Diego, Dept Pediat, Ctr Acad Res & Training Anthropogeny, Kavli Inst Brain & Mind,Archealizat Ctr, La Jolla, CA 92093 USA

[18] Univ Calif San Diego, Ctr Acad Res & Training Anthropogeny, Kavli Inst Brain & Mind, Archealizat Ctr,Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[19] Univ Calif San Diego, Autism Ctr Excellence, La Jolla, CA 92093 USA

来源：

NATURE GENETICS | 2022年 / 54卷 / 09期

基金：

荷兰研究理事会; 美国国家卫生研究院;

关键词：

DE-NOVO MUTATIONS; PATERNAL AGE; MENTAL-HEALTH; DISORDERS; COMMON; TRANSMISSION; EXPRESSION; FRAMEWORK; BURDEN; GENES;

D O I：

10.1038/s41588-022-01064-5

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes. Integrated analyses in a large collection of families provide insights into the combined effects of rare variants and polygenic risk on autism spectrum disorder.

引用

页码：1284 / +

页数：21

共 65 条

[1]

Antaki, PREPRINT

[2] SV2 : accurate structural variation genotyping and de novo mutation detection from whole genomes [J].

Antaki, Danny ;

Brandler, William M. ;

Sebat, Jonathan .

BIOINFORMATICS, 2018, 34 (10) :1774-1777

[3] Analysis of shared heritability in common disorders of the brain [J].

Anttila, Verneri ;

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Walters, Raymond K. ;

Bras, Jose ;

Duncan, Laramie ;

Escott-Price, Valentina ;

Falcone, Guido J. ;

Gormley, Padhraig ;

Malik, Rainer ;

Patsopoulos, Nikolaos A. ;

Ripke, Stephan ;

Wei, Zhi ;

Yu, Dongmei ;

Lee, Phil H. ;

Turley, Patrick ;

Grenier-Boley, Benjamin ;

Chouraki, Vincent ;

Kamatani, Yoichiro ;

Berr, Claudine ;

Letenneur, Luc ;

Hannequin, Didier ;

Amouyel, Philippe ;

Boland, Anne ;

Deleuze, Jean-Francois ;

Duron, Emmanuelle ;

Vardarajan, Badri N. ;

Reitz, Christiane ;

Goate, Alison M. ;

Huentelman, Matthew J. ;

Kamboh, M. Ilyas ;

Larson, Eric B. ;

Rogaeva, Ekaterina ;

St George-Hyslop, Peter ;

Hakonarson, Hakon ;

Kukull, Walter A. ;

Farrer, Lindsay A. ;

Barnes, Lisa L. ;

Beach, Thomas G. ;

Demirci, F. Yesim ;

Head, Elizabeth ;

Hulette, Christine M. ;

Jicha, Gregory A. ;

Kauwe, John S. K. ;

Kaye, Jeffrey A. ;

Leverenz, James B. ;

Levey, Allan I. ;

Lieberman, Andrew P. ;

Pankratz, Vernon S. ;

Poon, Wayne W. .

SCIENCE, 2018, 360 (6395) :1313-+

[4] Joint Contributions of Rare Copy Number Variants and Common SNPs to Risk for Schizophrenia [J].

Bergen, Sarah E. ;

Ploner, Alexander ;

Howrigan, Daniel ;

O'Donovan, Michael C. ;

Smoller, Jordan W. ;

Sullivan, Patrick F. ;

Sebat, Jonathan ;

Neale, Benjamin ;

Kendler, Kenneth S. .

AMERICAN JOURNAL OF PSYCHIATRY, 2019, 176 (01) :29-35

[5] An Expanded View of Complex Traits: From Polygenic to Omnigenic [J].

Boyle, Evan A. ;

Li, Yang I. ;

Pritchard, Jonathan K. .

CELL, 2017, 169 (07) :1177-1186

[6] Paternally inherited cis-regulatory structural variants are associated with autism [J].

Brandler, William M. ;

Antaki, Danny ;

Gujral, Madhusudan ;

Kleiber, Morgan L. ;

Whitney, Joe ;

Maile, Michelle S. ;

Hong, Oanh ;

Chapman, Timothy R. ;

Tan, Shirley ;

Tandon, Prateek ;

Pang, Timothy ;

Tang, Shih C. ;

Vaux, Keith K. ;

Yang, Yan ;

Harrington, Eoghan ;

Juul, Sissel ;

Turner, Daniel J. ;

Thiruvahindrapuram, Bhooma ;

Kaur, Gaganjot ;

Wang, Zhuozhi ;

Kingsmore, Stephen F. ;

Gleeson, Joseph G. ;

Bisson, Denis ;

Kakaradov, Boyko ;

Telenti, Amalio ;

Venter, J. Craig ;

Corominas, Roser ;

Toma, Claudio ;

Cormand, Bru ;

Rueda, Isabel ;

Guijarro, Silvina ;

Messer, Karen S. ;

Nievergelt, Caroline M. ;

Arranz, Maria J. ;

Courchesne, Eric ;

Pierce, Karen ;

Muotri, Alysson R. ;

Iakoucheva, Lilia M. ;

Hervas, Amaia ;

Scherer, Stephen W. ;

Corsello, Christina ;

Sebat, Jonathan .

SCIENCE, 2018, 360 (6386) :327-330

[7] Damaging de novo mutations diminish motor skills in children on the autism spectrum [J].

Buja, Andreas ;

Volfovsky, Natalia ;

Krieger, Abba M. ;

Lord, Catherine ;

Lash, Alex E. ;

Wigler, Michael ;

Iossifov, Ivan .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (08) :E1859-E1866

[8] Integrating single-cell transcriptomic data across different conditions, technologies, and species [J].

Butler, Andrew ;

Hoffman, Paul ;

Smibert, Peter ;

Papalexi, Efthymia ;

Satija, Rahul .

NATURE BIOTECHNOLOGY, 2018, 36 (05) :411-+

[9] PRSice-2: Polygenic Risk Score software for biobank-scale data [J].

Choi, Shing Wan ;

O'Reilly, Paul F. .

GIGASCIENCE, 2019, 8 (07)

[10] Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population [J].

Clarke, T-K ;

Lupton, M. K. ;

Fernandez-Pujals, A. M. ;

Starr, J. ;

Davies, G. ;

Cox, S. ;

Pattie, A. ;

Liewald, D. C. ;

Hall, L. S. ;

MacIntyre, D. J. ;

Smith, B. H. ;

Hocking, L. J. ;

Padmanabhan, S. ;

Thomson, P. A. ;

Hayward, C. ;

Hansell, N. K. ;

Montgomery, G. W. ;

Medland, S. E. ;

Martin, N. G. ;

Wright, M. J. ;

Porteous, D. J. ;

Deary, I. J. ;

McIntosh, A. M. .

MOLECULAR PSYCHIATRY, 2016, 21 (03) :419-425

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