02 May 2020

Genome-wide association studies have uncovered a thicket of risk variants for neurologic diseases, but in which cells are these disease genes doing their dirty work? Merging GWAS with gene-expression signatures across the mouse nervous system, researchers led by Jens Hjerling-Leffler and Patrick Sullivan of the Karolinska Institute in Stockholm predict the primary cell types driving genetic risk in multiple neurological disorders. In Alzheimer’s disease, unsurprisingly perhaps, microglia were the prime suspects. For Parkinson’s, dopaminergic neurons, gut neurons and, lo and behold, oligodendrocytes expressed a preponderance of risk genes. Published April 27 in Nature Genetics, the study could help researchers home in on precise cellular targets for each disease.

The majority of risk polymorphisms identified in GWAS reside within noncoding stretches of the genome. Scientists believe they influence expression of nearby genes, but in which cells? To find out, researchers have hatched several approaches. One assumes that to influence a given tissue or cell type, a variant must alter gene expression there. To test this, researchers obtain gene-expression profiles specific for different cell types, then ask how many of those signature genes are proximal to a given risk polymorphism. Cells that express the most genes near the polymorphism are more likely to be influenced by the genetic variants, the logic goes; hence those cells are more likely to drive disease risk (Skene et al., 2016; Finucane et al., 2018). 

Using this method, Hjerling-Leffler, Sullivan, and colleagues previously reported that out of 24 cell types sampled from four brain regions, gene expression in four types of neuron associated with schizophrenia variants (Skene et al., 2018). For the current study, first authors Julien Bryois and Nathan Skene expanded their survey to the entire nervous system and included variants that cause neurodegenerative disease.

The researchers built upon their recent, single-cell RNA-sequencing-based, gene-expression profiles of 39 cell types in the mouse central and peripheral nervous system (Zeisel et al., 2018). For each cell type, they determined the top 10 percent of genes most specific to those cells. They considered only those genes that have direct human homologs. Using data from 18 GWAS for brain disorders, the researchers then calculated how many risk variants for each disorder occurred near these cell-type specific genes.

For schizophrenia, the researchers found a preponderance of variants near genes expressed in excitatory neurons from the cortex, hippocampus, and amygdala, as well as inhibitory neurons in the striatum. Similar cell types were implicated in other psychiatric and cognitive disorders.

In contrast, neurological diseases including stroke, AD, and PD had distinct cellular-association patterns. They involved fewer cell types. Stroke risk variants associated with vascular smooth muscle cells, consistent with the vascular nature of ischemia. AD risk variants linked to microglia genes, although this association didn’t hold up to correction for multiple statistical comparisons. Hjerling-Leffler pointed out that this relatively weak association could relate to the pronounced differences between human and mouse microglia (May 2019 news; Hodge et al., 2019; Jan 2020 news). 

Top 10 Culprits in Parkinson’s. PD risk variants occurred near genes predominantly expressed in specific cell types. Cholinergic and dopaminergic neurons came out on top. Oddly, oligodendrocytes were second, enteric neurons third. Cells are ranked by strength of association. [Courtesy of Hjerling-Leffler et al., Nature Genetics, 2020.]

For PD, cholinergic and monoaminergic neurons—including dopaminergic neurons in the substantia nigra—drove the highest proportion of risk. Disease variants were also active in enteric neurons, a finding that meshes with the hypothesis that PD could start in the gut (Braak et al., 2003). Unexpectedly, oligodendrocytes were also strongly tied to PD risk.

The researchers confirmed their findings in several independent mouse and human gene-expression datasets. For example, in one human dataset with 15 different cell types from the cortex and hippocampus, the researchers again found oligodendrocytes implicated in PD. Cholinergic, monoaminergic, and enteric neurons were not sampled in that dataset. In a separate human dataset that sampled 35 different cell types from the visual cortex, frontal cortex, and cerebellum, microglia were tied to AD risk. No cell type was tied to PD risk in this dataset, but the relevant brain regions were not sampled.

To further probe the curious role of oligodendrocytes, the researchers took stock of genes—not genetic variants—differentially expressed in postmortem substantia nigra samples from PD cases versus controls. They examined data from three case-control studies. While most of the differentially expressed genes in dopaminergic neurons were turned down in people with PD, in oligodendrocytes, the opposite was true and differentially expressed genes ramped up in PD. Data from neuropathological studies indicated that while this suite of oligodendrocyte genes were upregulated early on—in Braak stages I to II—the downregulated signature in dopaminergic neurons did not emerge until later stages. Together, the findings suggest an uptick in oligodendrocyte activity early in disease, followed by a slide in dopaminergic neuron expression later.

Hjerling-Leffler told Alzforum that he hopes the study will shine a light on which cell types are causally implicated in a given disease, as opposed to which cells are merely responding to the disease process.

What oligodendrocytes do in PD clearly needs further study, Hjerling-Leffler said. While it is unclear how these myelinating cells are involved, he hypothesized that they could be protective early in disease, and hence rev up activity. Perhaps genetic variants hamper this process. He plans to investigate how disease variants interfere with specific functions of these cells.—Jessica Shugart

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References

News Citations

1. When It Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM? 23 May 2019
2. Human and Mouse Microglia React Differently to Amyloid 17 Jan 2020

Paper Citations

1. Skene NG, Grant SG. Identification of Vulnerable Cell Types in Major Brain Disorders Using Single Cell Transcriptomes and Expression Weighted Cell Type Enrichment. Front Neurosci. 2016;10:16. Epub 2016 Jan 27 PubMed.
2. Finucane HK, Reshef YA, Anttila V, Slowikowski K, Gusev A, Byrnes A, Gazal S, Loh PR, Lareau C, Shoresh N, Genovese G, Saunders A, Macosko E, Pollack S, Brainstorm Consortium, Perry JR, Buenrostro JD, Bernstein BE, Raychaudhuri S, McCarroll S, Neale BM, Price AL. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat Genet. 2018 Apr;50(4):621-629. Epub 2018 Apr 9 PubMed.
3. Skene NG, Bryois J, Bakken TE, Breen G, Crowley JJ, Gaspar HA, Giusti-Rodriguez P, Hodge RD, Miller JA, Muñoz-Manchado AB, O'Donovan MC, Owen MJ, Pardiñas AF, Ryge J, Walters JT, Linnarsson S, Lein ES, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sullivan PF, Hjerling-Leffler J. Genetic identification of brain cell types underlying schizophrenia. Nat Genet. 2018 Jun;50(6):825-833. Epub 2018 May 21 PubMed.
4. Zeisel A, Hochgerner H, Lönnerberg P, Johnsson A, Memic F, van der Zwan J, Häring M, Braun E, Borm LE, La Manno G, Codeluppi S, Furlan A, Lee K, Skene N, Harris KD, Hjerling-Leffler J, Arenas E, Ernfors P, Marklund U, Linnarsson S. Molecular Architecture of the Mouse Nervous System. Cell. 2018 Aug 9;174(4):999-1014.e22. PubMed.
5. Hodge RD, Bakken TE, Miller JA, Smith KA, Barkan ER, Graybuck LT, Close JL, Long B, Johansen N, Penn O, Yao Z, Eggermont J, Höllt T, Levi BP, Shehata SI, Aevermann B, Beller A, Bertagnolli D, Brouner K, Casper T, Cobbs C, Dalley R, Dee N, Ding SL, Ellenbogen RG, Fong O, Garren E, Goldy J, Gwinn RP, Hirschstein D, Keene CD, Keshk M, Ko AL, Lathia K, Mahfouz A, Maltzer Z, McGraw M, Nguyen TN, Nyhus J, Ojemann JG, Oldre A, Parry S, Reynolds S, Rimorin C, Shapovalova NV, Somasundaram S, Szafer A, Thomsen ER, Tieu M, Quon G, Scheuermann RH, Yuste R, Sunkin SM, Lelieveldt B, Feng D, Ng L, Bernard A, Hawrylycz M, Phillips JW, Tasic B, Zeng H, Jones AR, Koch C, Lein ES. Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019 Sep;573(7772):61-68. Epub 2019 Aug 21 PubMed.
6. Braak H, Rüb U, Gai WP, Del Tredici K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm. 2003 May;110(5):517-36. PubMed.

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