Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights

被引：294

作者：

Gusev, Alexander ^{[1
,2
,3
]}

Mancuso, Nicholas ^{[4
]}

Won, Hyejung ^{[5
]}

Kousi, Maria ^{[6
]}

Finucane, Hilary K. ^{[1
,2
,7
]}

Reshef, Yakir ^{[8
]}

Song, Lingyun ^{[9
,10
]}

Safi, Alexias ^{[9
,10
]}

McCarroll, Steven ^{[11
,12
]}

Neale, Benjamin M. ^{[2
,12
,13
,14
]}

Ophoff, Roel A. ^{[15
,16
]}

O'Donovan, Michael C. ^{[17
]}

Crawford, Gregory E. ^{[9
,10
]}

Geschwind, Daniel H. ^{[15
,18
,19
]}

Katsanis, Nicholas

Sullivan, Patrick F. ^{[20
,21
,22
]}

Pasaniuc, Bogdan ^{[18
]}

Price, Alkes L. ^{[1
,2
]}

机构：

[1] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

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

[3] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

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

[6] Duke Univ, Med Ctr, Ctr Human Dis Modeling, Durham, NC USA

[7] MIT, Dept Math, Cambridge, MA 02139 USA

[8] Harvard Univ, Dept Comp Sci, Cambridge, MA 02138 USA

[9] Duke Univ, Ctr Genom & Computat Biol, Durham, NC USA

[10] Duke Univ, Med Ctr, Dept Pediat, Div Med Genet, Durham, NC 27710 USA

[11] Harvard Med Sch, Dept Genet, Boston, MA USA

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

[13] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[14] Harvard Med Sch, Boston, MA USA

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

[16] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, Utrecht, Netherlands

[17] Cardiff Univ, MRC Ctr Psychiat Genet & Genom, Cardiff, S Glam, Wales

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

[19] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Program Neurobehav Genet, Los Angeles, CA 90095 USA

[20] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[21] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA

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

来源：

NATURE GENETICS | 2018年 / 50卷 / 04期

关键词：

GENE-EXPRESSION; PARTITIONING HERITABILITY; POLYGENIC RISK; VARIANTS; 16P11.2; TRAITS; HUMANS; COMMON; IDENTIFICATION; STATISTICS;

D O I：

10.1038/s41588-018-0092-1

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.

引用

页码：538 / +

页数：13

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