NEW YORK – By combining the results of genome-wide association studies with transcriptome data, researchers have homed in on the cell types affected by complex brain disorders, including Parkinson's disease.
As they reported in Nature Genetics Monday, a Karolinska Institute-led team of researchers has now identified tissue and cell types affected by complex brain traits. Genome-wide association studies have highlighted numerous loci associated with various complex brain disorders, but the tissue and cell types in which these variants might have their effect is not always clear.
The researchers linked psychiatric disorders to projecting excitatory and inhibitory neurons, but in particular found Parkinson's disease to be associated with not only cholinergic and monoaminergic neurons, but also enteric neurons — bolstering a theory that the malady may start in the gut — and, unexpectedly, oligodendrocytes.
"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," senior author Patrick Sullivan from Karolinska and his colleagues wrote in their paper.
They combined summary statistics for 18 GWAS of brain-related complex traits and, for comparison, eight other, non-central nervous system traits or disorders with bulk tissue RNA sequencing data from the Genotype-Tissue Expression (GTEx) project. Using two methods, MAGMA and LDSC, they homed in on tissues implicated in those GWAS.
The non-brain-related traits were associated with the expected tissues — type 2 diabetes was linked to the pancreas, while stroke and coronary artery disease were associated with blood vessels.
Thirteen brain-related traits were associated with one or more of the GTEx brain regions. For example, schizophrenia, intelligence, and major depressive disorder were associated with the brain cortex, frontal cortex, or anterior cingulate cortex, while Parkinson's disease was linked, as expected, to the substantia nigra and spinal cord.
They further mapped these brain-related traits to particular cell types using mouse gene expression data on more than three dozen cell types. They argued this approach was valid because they focused on protein-coding genes with one-to-one mouse to human orthologs — noting that there's high correlation in gene expression by cell type across species — and because they later replicated the mouse findings in human samples.
In agreement with their previous work, the researchers found schizophrenia to be associated with telencephalon projecting inhibitory neurons and telencephalon projecting excitatory neurons.
Neurological disorders, meanwhile, implicated fewer cell types and had a distinct pattern of association from psychiatric disorders, suggesting neurological disorders have limited functional overlap with psychiatric disorders.
Parkinson's disease was significantly associated with cholinergics and monoaminergic neurons, which the researchers noted are known to degenerate in the disease.
In addition, it was also associated with enteric neurons. This, they noted, is consistent with Braak's hypothesis that suggests Parkinson's disease could start in the gut and move to the brain through the vagus nerve.
Unexpectedly, oligodendrocytes were also associated with Parkinson's disease, which indicates a potential glial component to the disorder.
They replicated these findings in additional single-cell RNA-seq datasets from mice and humans. Additionally, in post-mortem human brain samples, they noted differences in gene expression at various Parkinson's disease stages that suggest that oligodendrocytes become involved in disease early on and could even play a causal role.
"Our findings suggest that alterations in oligodendrocytes occur at an early stage of disease, which precedes neurodegeneration in the substantia nigra, arguing for a key role of this cell type in Parkinson's disease etiology," the researchers wrote.