No rare deleterious variants from , , and are associated with essential tremor.

OBJECTIVE

To assess the contribution of variants in , , and as essential tremor (ET) predisposing factors following their association in a 2-stage genome-wide association study (GWAS).

METHODS

The coding regions of these genes was examined for the presence of rare variants using two approaches: (1) Looking at whole-exome and whole-genome sequencing data of 14 autosomal dominant multiplex ET families. (2) Conducting a targeted massive parallel sequencing to examine the three genes in cohorts of 269 ET cases and 287 control individuals. The cumulative impact of rare variants was assessed using SKAT-O analyses using (1) all variants, (2) only rare variants, and (3) only the rare variants altering the mRNA.

RESULTS

Thirty-four variants were identified. No difference emerged regarding the distributions of individual variants (or gene) between cases and controls.

CONCLUSION

No rare exonic variants further validated one of these genes as a risk factor for ET. The recent GWAS offers promising avenues, but the genetic heterogeneity of ET is nonetheless challenging for the validation of risk factors, and ultimately larger cohorts of cases should help to overcome this task.