Single-cell expression QTL analyses of the human cerebellum reveal vulnerability of oligodendrocytes in essential tremor.

Essential tremor, a movement disorder characterized by an upper-limb postural and action tremor, is among the most common neurological disorders, affecting 1% of the population worldwide. Despite strong evidence for genetic factors driving the etiology of essential tremor, the underlying pathophysiology remains poorly understood. To understand the effects of genetic risk factors in essential tremor on the cerebellum, the brain region suspected to be affected by the disease, we built a population-scale single-cell atlas of the human cerebellar cortex comprising more than 1 million cells from 109 individuals. Here, using single-cell expression quantitative trait loci and Mendelian randomization, we show that essential-tremor-associated variants in the BACE2 locus are causally linked to its downregulation in cerebellar oligodendrocytes. We highlight a genetically vulnerable population of BACE2-expressing immature oligodendrocytes, suggestive of demyelination. We also identify dysfunctional processes affecting interactions between neuronal populations and oligodendrocytes in essential tremor. Our findings suggest a crucial role for cerebellar oligodendrocytes in the pathogenesis of essential tremor.