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

Abstract

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.

Figure 1:

Study design and tissue-level associations. Heat map of trait – tissue/cell types associations (−log₁₀P) for the selected traits. (A) Trait – tissue/cell types associations were performed using MAGMA and LDSC (testing for enrichment in genetic association of the top 10% most specific genes in each tissue/cell type). (B) Tissue – trait associations for selected brain related traits. (C) Tissue – trait associations for selected non-brain related traits. (D) The mean strength of association (−log₁₀P) of MAGMA and LDSC is shown and the bar color indicates whether the tissue is significantly associated with both methods, one method or none (significance threshold: 5% false discovery rate).

Figure 2:

Association of selected brain related traits with cell types from the entire nervous system. 841 Associations of the top 10 most associated cell types are shown. (A) Conditional analysis results for 842 Parkinson’s disease using MAGMA. The label indicates the cell type the association analysis is being 843 conditioned on. (B) The mean strength of association (−log₁₀P) of MAGMA and LDSC is shown and 844 the bar color indicates whether the cell type is significantly associated with both methods, one method 845 or none (significance threshold: 5% false discovery rate).

Figure 3:

Replication of cell type – trait associations in mouse datasets. Tissue – trait associations are shown for the 10 most association cell types among 88 cell types from 9 different brain regions. (A) Tissue – trait associations are shown for the 10 most association cell types among 24 cell types from 5 different brain regions. (B) The mean strength of association (−log₁₀P) of MAGMA and LDSC is shown and the bar color indicates whether the cell type is significantly associated with both methods, one method or none (significance threshold: 5 % false discovery rate).

Figure 4:

Human replication of cell type – trait associations. Cell type - trait associations for 15 cell types (derived from single-nuclei RNA-seq) from 2 different brain regions (cortex, hippocampus). (A) Cell type - trait associations for 31 cell types (derived from single-nuclei RNA-seq) from 3 different brain regions (frontal cortex, visual cortex and cerebellum). (B) The mean strength of association (−log₁₀P) of MAGMA and LDSC is shown and the bar color indicates whether the cell type is significantly associated with both methods, one method or none (significance threshold: 5% false discovery rate). INT (intelligence), SCZ (schizophrenia), EDU (educational attainment), NEU (neuroticism), BMI (body mass index), BIP (bipolar disorder), MDD (Major depressive disorder), MEN (age at menarche), ASD (autism spectrum disorder), MIG (migraine), PAR (Parkinson’s disease), ADHD (attention deficit hyperactivity disorder), ICV (intracranial volume), HIP (hippocampal volume), AN (anorexia nervosa), ALZ (Alzheimer’s disease), ALS (amyotrophic lateral sclerosis), STR (stroke).

Figure 5:

Enrichment of Parkinson’s disease differentially expressed genes in cell types from the substantia nigra. Enrichment of the 500 most up/down regulated genes (Braak stage 0 vs Braak stage 1—2, 3—4 and 5—6, as well as cases vs controls) in postmortem human substantia nigra gene expression samples. The enrichments were obtained using EWCE. A star shows significant enrichments after multiple testing correction (P<0.05/(25*6).