JAMA Neurology: 5 genome-wide significant loci associated with essential tremor risk

Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population over the age of 65
.
Common variants are thought to contribute to ET susceptibility, but no reliable variants have been identified
.

Essential tremor (ET) is a complex neurological disorder that affects 1% of the general population and up to 5% of people over the age of 65
.
ET is clinically characterized by bilateral, highly symmetrical motor or postural tremors, which can greatly reduce quality of life and impair daily functioning
.
Previous studies have suggested that the cerebellum may be an important region for ET
.
Specifically, Purkinje cell abnormalities were observed in postmortem brain tissue of ET patients
.
Several transcriptomic studies and imaging studies have also highlighted the importance of the cerebellum in ET
.

Calwing Liao et al.
presented a genome-wide meta-analysis using a cohort of 7177 ET individuals and 475 877 control individuals to identify the first genome-wide significant loci for ET
.
In addition, novel loci were identified involving tissue-related genes and significant genetic overlap between Parkinson's disease (PD) and ET was found
.
This report supports the heritability of ET and involves novel disease-associated loci and genes
.

The study used inverse variance meta-analysis to pool cohorts
.
As part of an ongoing study, a multicentre sample from the European population was collected from January 2010 to September 2019
.
Included patients were those who were clinically diagnosed or reported to have ET
.
Patients in the control group were those who had not been diagnosed or reported having ET
.
Data on 4830 054 patients out of 485 250 patients passed data quality control
.
Genotyping of common variants associated with ET risk
.

Finally, 483054 individuals were included, of which 7177 had ET (3693 [51.
46%] women; mean age 62.
66±15.
12 years) and 475 877 control individuals (253 785 [53.
33%] women; mean age 56.
40 ±17.
6 years)
.

Five independent genome-wide significant loci were identified and associated with approximately 18% of ET heritability
.

Major single nucleotide variants (SNVs) at genome-wide significant loci in 7177 essential tremor patients and 475 877 control patients

Functional analysis found significant enrichment in the cerebellar hemisphere, cerebellum, and axogenesis pathways
.

Genetic correlation (r), a measure of the degree of genetic overlap, revealed significant covariant overlap between Parkinson's disease (r, 0.
28; P = 2.
38 10 8 ) and depression (r, 0.
12; P = 9.
78 10 4 )
.

Mirror Manhattan plots of transcriptome-wide associations in essential tremor

Another fine-mapping of transcriptome-wide associations identified genes such as BACE2, LRRN2, DHRS13 and LINC00323 that have been identified in disease-associated brain regions such as the cerebellum
.

This study identified five ET genome-wide significant loci, suggesting that approximately 18% of ET heritability may be explained by common variation
.
The meta-analysis involved genes such as BACE2 and reinforced the importance of the cerebellum in the etiology of ET
.
The results also showed that approximately 30% of genetic variants overlap with PD, and there is no genetic evidence that ET is a risk factor for PD
.

original source

Liao C, Castonguay C, Heilbron K, et al.
Association of Essential Tremor With Novel Risk Loci : A Genome-Wide Association Study and Meta-analysis.
 JAMA Neurol.
 Published online January 04, 2022.
doi:10.
1001/jamaneurol.
2021.
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