De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

被引：123

作者：

Dong, Shan ^{[1
,2
]}

Walker, Michael F. ^{[3
]}

Carriero, Nicholas J. ^{[4
]}

DiCola, Michael ^{[5
]}

Willsey, A. Jeremy ^{[2
,3
]}

Ye, Adam Y. ^{[1
,6
]}

Waqar, Zainulabedin ^{[7
]}

Gonzalez, Luis E. ^{[7
]}

Overton, John D. ^{[8
,9
]}

Frahm, Stephanie ^{[5
]}

Keaney, John F., III ^{[10
]}

Teran, Nicole A. ^{[7
]}

Dea, Jeanselle ^{[3
]}

Mandell, Jeffrey D. ^{[3
]}

Bal, Vanessa Hus ^{[3
]}

Sullivan, Catherine A. ^{[7
]}

DiLullo, Nicholas M. ^{[7
]}

Khalil, Rehab O. ^{[3
,11
]}

Gockley, Jake ^{[2
]}

Yuksel, Zafer ^{[12
]}

Sertel, Sinem M. ^{[13
]}

Ercan-Sencicek, A. Gulhan ^{[14
]}

Gupta, Abha R. ^{[7
,15
]}

Mane, Shrikant M. ^{[8
]}

Sheldon, Michael ^{[16
,17
]}

Brooks, Andrew I. ^{[5
]}

Roeder, Kathryn ^{[18
,19
]}

Devlin, Bernie ^{[20
]}

State, Matthew W. ^{[2
,3
,7
,21
]}

Wei, Liping ^{[1
,6
]}

Sanders, Stephan J. ^{[2
,3
]}

机构：

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

[2] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA

[3] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94158 USA

[4] Yale Univ, Dept Comp Sci, WM Keck Biotechnol Resource Lab, Biomed High Performance Comp Ctr, New Haven, CT 06520 USA

[5] Rutgers State Univ, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA

[6] Natl Inst Biol Sci, Beijing 102206, Peoples R China

[7] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06520 USA

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

[9] Regeneron Genet Ctr, Tarrytown, NY 10591 USA

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

[11] Natl Res Ctr, Dept Res Children Special Needs, Cairo 11787, Egypt

[12] Gulhane Mil Med Acad, Dept Med Genet, TR-06010 Ankara, Turkey

[13] Bilkent Univ, Dept Mol Biol & Genet, TR-06800 Ankara, Turkey

[14] Yale Univ, Dept Comp Sci, Yale Neurogenet Program, Dept Neurosurg, New Haven, CT 06520 USA

[15] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA

[16] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA

[17] Rutgers State Univ, Inst Human Genet, Piscataway, NJ 08854 USA

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

[19] Carnegie Mellon Univ, Ray & Stephanie Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA

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

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

来源：

CELL REPORTS | 2014年 / 9卷 / 01期

基金：

中国国家自然科学基金;

关键词：

ZONE PROTEIN RIM1-ALPHA; MUTATIONS; NETWORKS; GENES;

D O I：

10.1016/j.celrep.2014.08.068

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 3 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

引用

页码：16 / 23

页数：8

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