PT  - JOURNAL ARTICLE
AU  - Julien Bryois
AU  - Nathan G. Skene
AU  - Thomas Folkmann Hansen
AU  - Lisette Kogelman
AU  - Hunna J. Watson
AU  - Zijing Liu
AU  - Eating Disorders Working Group of the Psychiatric Genomics Consortium
AU  - International Headache Genetics Consortium
AU  - 23andMe Research Team
AU  - Leo Brueggeman
AU  - Gerome Breen
AU  - Cynthia M. Bulik
AU  - Ernest Arenas
AU  - Jens Hjerling-Leffler
AU  - Patrick F. Sullivan
TI  - Genetic Identification of Cell Types Underlying Brain Complex Traits Yields Novel Insights Into the Etiology of Parkinson’s Disease
AID  - 10.1101/528463
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 528463
4099  - http://biorxiv.org/content/early/2019/12/16/528463.short
4100  - http://biorxiv.org/content/early/2019/12/16/528463.full
AB  - Genome-wide association studies (GWAS) have discovered hundreds of loci associated with complex brain disorders, and provide the best current insights into the etiology of these idiopathic traits. However, it remains unclear in which cell types these variants are active, which is essential for understanding etiology and subsequent experimental modeling. Here we integrate GWAS results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying psychiatric disorders, neurological diseases, and brain complex traits. We show that psychiatric disorders are predominantly associated with cortical and hippocampal excitatory neurons, as well as medium spiny neurons from the striatum. Cognitive traits were generally associated with similar cell types but their associations were driven by different genes. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, we found that Parkinson’s disease is not only genetically associated with cholinergic and monoaminergic neurons (which include dopaminergic neurons from the substantia nigra) but also with neurons from the enteric system 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.