Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

被引：290

作者：

Ruzzo, Elizabeth K. ^{[1
,2
]}

Perez-Cano, Laura ^{[3
]}

Jung, Jae-Yoon ^{[4
,5
]}

Wang, Lee-kai ^{[1
,2
]}

Kashef-Haghighi, Dorna ^{[4
,5
,9
]}

Hartl, Chris ^{[6
]}

Singh, Chanpreet ^{[7
]}

Xu, Jin ^{[7
]}

Hoekstra, Jackson N. ^{[1
,2
]}

Leventhal, Olivia ^{[1
,2
]}

Leppa, Virpi M. ^{[3
,10
]}

Gandal, Michael J. ^{[1
,2
]}

Paskov, Kelley ^{[4
,5
]}

Stockham, Nate ^{[4
,5
]}

Polioudakis, Damon ^{[3
]}

Lowe, Jennifer K. ^{[1
,2
]}

Prober, David A. ^{[7
]}

Geschwind, Daniel H. ^{[1
,2
,3
,8
]}

Wall, Dennis P. ^{[4
,5
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Ctr Autism Res & Treatment, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[4] Stanford Univ, Dept Pediat, Div Syst Med, Stanford, CA 94305 USA

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

[6] Univ Calif Los Angeles, Bioinformat IDP, Los Angeles, CA USA

[7] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[9] Illumina Inc, Illumina Artificial Intelligence Lab, San Diego, CA USA

[10] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

来源：

CELL | 2019年 / 178卷 / 04期

关键词：

COPY-NUMBER VARIATION; SPECTRUM DISORDER; STRUCTURAL VARIATION; CANDIDATE GENES; MUTATIONS; DISCOVERY; VARIANTS; RARE; HERITABILITY; FRAMEWORK;

D O I：

10.1016/j.cell.2019.07.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

引用

页码：850 / +

页数：43

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