Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

被引：922

作者：

Sanders, Stephan J. ^{[1
]}

Xin He ^{[2
]}

Willsey, A. Jeremy ^{[1
]}

Ercan-Sencicek, A. Gulhan ^{[3
]}

Samocha, Kaitlin E. ^{[4
,5
,6
,7
,8
]}

Cicek, A. Ercument ^{[9
,10
]}

Murtha, Michael T. ^{[3
]}

Bal, Vanessa H. ^{[1
]}

Bishop, Somer L. ^{[1
]}

Shan Dong ^{[11
]}

Goldberg, Arthur P. ^{[12
,13
]}

Cai Jinlu ^{[12
,13
]}

Keaney, John F., III ^{[14
]}

Klei, Lambertus ^{[15
]}

Mandell, Jeffrey D. ^{[1
]}

Moreno-De-Luca, Daniel ^{[16
]}

Poultney, Christopher S. ^{[12
,13
]}

Robinson, Elise B. ^{[4
,5
,6
,7
]}

Smith, Louw ^{[1
]}

Solli-Nowlan, Tor ^{[17
]}

Su, Mack Y. ^{[18
]}

Teran, Nicole A. ^{[19
]}

Walker, Michael F. ^{[1
]}

Werling, Donna M. ^{[1
]}

Beaudet, Arthur L. ^{[20
]}

Cantor, Rita M. ^{[21
,22
]}

Fombonne, Eric ^{[23
,24
]}

Geschwind, Daniel H. ^{[25
,26
]}

Grice, Dorothy E. ^{[13
]}

Lord, Catherine ^{[27
]}

Lowe, Jennifer K. ^{[25
,26
]}

Mane, Shrikant M. ^{[28
]}

Martin, Donna M. ^{[29
,30
]}

Morrow, Eric M. ^{[31
,32
]}

Talkowski, Michael E. ^{[33
,34
,35
]}

Sutcliffe, James S. ^{[36
]}

Walsh, Christopher A. ^{[37
,38
,39
]}

Yu, Timothy W. ^{[37
,38
,39
]}

Ledbetter, David H. ^{[40
]}

Martin, Christa Lese ^{[40
]}

Cook, Edwin H. ^{[41
]}

Buxbaum, Joseph D. ^{[12
,13
]}

Daly, Mark J. ^{[4
,5
,6
,7
]}

Devlin, Bernie ^{[15
]}

Roeder, Kathryn ^{[42
]}

State, Matthew W. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA

[2] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[3] Yale Univ, Program Neurogenet, Sch Med, Dept Neurosurg, New Haven, CT 06520 USA

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

[5] Harvard Univ, Sch Med, Boston, MA 02114 USA

[6] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[7] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[8] Harvard Univ, Sch Med, Program Genet & Genom, Biol & Biomed Sci, Boston, MA 02114 USA

[9] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15213 USA

[10] Bilkent Univ, Dept Comp Engn, TR-0680 Ankara, Turkey

[11] Peking Univ, Sch Life Sci, Ctr Bioinformat, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China

[12] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[13] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[14] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06520 USA

[15] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA

[16] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA

[17] TheLab Inc, Los Angeles, CA 90068 USA

[18] Harvard Univ, Program Biophys, Boston, MA 02115 USA

[19] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA

[20] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

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

[22] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA

[23] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA

[24] Oregon Hlth & Sci Univ, Inst Dev & Disabil, Portland, OR 97239 USA

[25] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Semel Inst,Neurogenet Program, Los Angeles, CA 90095 USA

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

[27] Weill Cornell Med Coll, Ctr Autism & Dev Brain, White Plains, NY 10605 USA

[28] Yale Univ, Sch Med, Yale Ctr Genom Anal, New Haven, CT 06520 USA

[29] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA

[30] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[31] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA

[32] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA

[33] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Neurol, Boston, MA 02114 USA

[34] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[35] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[36] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Mol Neurosci, Nashville, TN 37232 USA

[37] Childrens Hosp Boston, Howard Hughes Med Inst, Boston, MA 02115 USA

[38] Childrens Hosp Boston, Div Genet & Genom, Boston, MA 02115 USA

[39] Harvard Univ, Sch Med, Ctr Life Sci, Neurol & Pediat, Boston, MA 02115 USA

[40] Geisinger Hlth Syst, Autism & Dev Med Inst, Danville, PA 17822 USA

[41] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60637 USA

[42] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

来源：

NEURON | 2015年 / 87卷 / 06期

基金：

加拿大健康研究院;

关键词：

COPY-NUMBER VARIATION; DE-NOVO MUTATIONS; HIDDEN-MARKOV MODEL; TRUNCATING MUTATIONS; STRUCTURAL VARIATION; GENE; RARE; IMPLICATE; PATHWAYS; ASSOCIATION;

D O I：

10.1016/j.neuron.2015.09.016

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR <= 0.1).

引用

页码：1215 / 1233

页数：19

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