Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson's disease

被引：216

作者：

Bryois, Julien ^{[1
]}

Skene, Nathan G. ^{[2
,3
,4
,5
]}

Hansen, Thomas Folkmann ^{[6
,7
,8
]}

Kogelman, Lisette J. A. ^{[6
]}

Watson, Hunna J. ^{[9
,10
,11
]}

Liu, Zijing ^{[4
,5
]}

Brueggeman, Leo ^{[12
]}

Breen, Gerome ^{[13
,14
]}

Bulik, Cynthia M. ^{[1
,9
,15
]}

Arenas, Ernest ^{[2
]}

Hjerling-Leffler, Jens ^{[2
]}

Sullivan, Patrick F. ^{[1
,16
]}

机构：

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

[2] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden

[3] UCL Inst Neurol, Queen Sq, London, England

[4] Imperial Coll, Dept Med, Div Brain Sci, London, England

[5] Imperial Coll, UK Dementia Res Inst, London, England

[6] Copenhagen Univ Hosp, Danish Headache Ctr, Dept Neurol, Glostrup, Denmark

[7] Copenhagen Univ Hosp MHC Sct Hans, Inst Biol Psychiat, Roskilde, Denmark

[8] Univ Copenhagen, Ctr Prot Res, Novo Nordic Fdn, Copenhagen, Denmark

[9] Univ North Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA

[10] Curtin Univ, Sch Psychol, Perth, WA, Australia

[11] Univ Western Australia, Sch Med, Div Paediat, Perth, WA, Australia

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

[13] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, MRC, London, England

[14] South London & Maudsley Natl Hlth Serv Trust, Biomed Res Ctr, Natl Inst Hlth Res, London, England

[15] Univ North Carolina, Dept Nutr, Chapel Hill, NC 27515 USA

[16] Univ North Carolina, Dept Genet, Chapel Hill, NC 27515 USA

来源：

NATURE GENETICS | 2020年 / 52卷 / 05期

基金：

英国医学研究理事会; 瑞典研究理事会; 英国惠康基金; 瑞士国家科学基金会; 欧盟地平线“2020”;

关键词：

GENOME-WIDE ASSOCIATION; ENTERIC NERVOUS-SYSTEM; RISK LOCI; METAANALYSIS; NUCLEUS; ALZHEIMERS; IMMUNITY; NEURONS; TISSUES; HERITABILITY;

D O I：

10.1038/s41588-020-0610-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson's disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson's disease. Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson's disease.

引用

页码：482 / +

页数：25

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