Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

被引：163

作者：

Zhou, Xueya ^{[1
,2
]}

Feliciano, Pamela ^{[3
]}

Shu, Chang ^{[1
,2
]}

Wang, Tianyun ^{[4
,5
,6
,7
]}

Astrovskaya, Irina ^{[3
]}

Hall, Jacob B. ^{[3
]}

Obiajulu, Joseph U. ^{[1
,2
]}

Wright, Jessica R. ^{[3
]}

Murali, Shwetha C. ^{[4
,5
]}

Xu, Simon Xuming ^{[3
]}

Brueggeman, Leo ^{[9
]}

Thomas, Taylor R. ^{[9
]}

Marchenko, Olena ^{[3
]}

Fleisch, Christopher ^{[3
]}

Barns, Sarah D. ^{[3
]}

Snyder, LeeAnne Green ^{[3
]}

Han, Bing ^{[3
]}

Chang, Timothy S. ^{[10
]}

Turner, Tychele N. ^{[11
]}

Harvey, William T. ^{[4
]}

Nishida, Andrew ^{[12
]}

O'Roak, Brian J. ^{[12
]}

Geschwind, Daniel H. ^{[10
]}

Michaelson, Jacob J. ^{[9
]}

Volfovsky, Natalia ^{[3
]}

Eichler, Evan E. ^{[4
,8
]}

Shen, Yufeng ^{[2
,13
]}

Chung, Wendy K. ^{[1
,3
,14
]}

机构：

[1] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA

[2] Columbia Univ, Dept Syst Biol, Med Ctr, New York, NY USA

[3] Simons Fdn, New York, NY 10010 USA

[4] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA

[5] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Med Genet,Dept Med Genet, Beijing, Peoples R China

[6] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Neurosci Res Inst,Dept Neurobiol, Beijing, Peoples R China

[7] Minist Educ China & Natl Hlth Commiss China, Key Lab Neurosci, Beijing, Peoples R China

[8] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

[9] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA

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

[11] Washington Univ, Dept Genet, St Louis, MO 63110 USA

[12] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[13] Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY USA

[14] Columbia Univ, Dept Med, Med Ctr, New York, NY 10032 USA

来源：

NATURE GENETICS | 2022年 / 54卷 / 09期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-TRUNCATING VARIANTS; COPY NUMBER VARIANTS; OF-FUNCTION VARIANTS; RARE; SCHIZOPHRENIA; EXPRESSION; DISORDER; KNOWLEDGEBASE; TRANSLOCATION; HERITABILITY;

D O I：

10.1038/s41588-022-01148-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 x10(-6)), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P =1.9 x10(-6)). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

引用

页码：1305 / +

页数：31

共 2 条

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