Essential tremor (ET) is one of the most common movement disorders, with a prevalence (age ≥40 years) estimated to be 4.0%. The underlying etiologies and disease mechanisms are not well understood. Several clinical studies suggest an association between ET and Parkinson’s disease (PD) [1
] and recent post-mortem studies have reported brainstem Lewy bodies (mainly in the locus ceruleus) in some ET cases [2
]. These clinical and post-mortem data suggest that ET may, in some cases, share similar disease mechanisms with PD. These observations provide a rationale to evaluate association between PD genetic risk factors and ET, particularly with rest tremor.
Recent studies have investigated whether genetic risk factors that are common in PD may also contribute to the genetic etiology of ET. Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene are associated with both familial and sporadic PD [3
] with G2019S, one the most frequently reported of these mutations (2–5% of Caucasian PD cases). To date, four studies have evaluated an association with ET by genotyping specific LRRK2 mutations or variants (G2019S, I2012T, I2020T, G2385R and P755L) in patients with ET [5
]. We and others have shown that mutations in the beta-Glucocerebrosidase (GBA) gene are associated with PD and Dementia with Lewy bodies and that GBA mutation status is significantly associated with the presence of cortical Lewy bodies [9
]. The GBA gene has not previously been evaluated as a candidate susceptibility gene for ET.
Our rationale for studying LRRK2 and GBA rather than other PD linked genes (a-synuclein, parkin, DJ-1 and PINK1) is that mutations in these genes represent two of the most significant susceptibility genes/risk factors identified to date in PD populations worldwide and a comprehensive analysis of these genes has not previously been performed in ET.
One motivation for the current study was that, in addition to the availability of a large sample of several hundred ET case as well as control bloods, we capitalized on the availability of a large sample of recently-collected ET brains in the Essential Tremor Centralized Brain Repository, which represents the largest collection of ET brains. These post-mortem analyses provided several unique opportunities. First, approximately 30–50% of “ET” cases are misdiagnosed, with most of these cases having PD. The demonstrated absence of Lewy bodies in the substantia nigra pars compacta in our autopsy ET cases minimized the possibility of such diagnostic misclassification. Second, a number of these ET brains had Lewy bodies restricted to the locus ceruleus. Whether these individuals are at increased risk for developing clinical–pathological PD is an open question. Therefore, it was added interest to examine PD-associated genetic markers in this sub-sample of ET cases.
We conducted three types of analyses. First, in 564 living subjects (275 ET cases [including 42 [15.3%] with rest tremor on examination and 233 [84.7%] without rest tremor] and 289 controls) and 24 ET brains (including 3 [12.5%] with brainstem Lewy bodies and 21 [87.5%] without Lewy bodies), we evaluated the frequency of 4 LRRK2 mutations (G2019S, I2020T, R1441C and Y1699C) and 2 rare LRRK2 variants (I1122V, L1114L) that have been reported in PD. Second, in the same living subjects, we performed a case–control association analysis to evaluate the frequency of 19 LRRK2 SNPs that span the entire LRRK2 gene. Third, in a subset of living subjects (93 AJ cases and 62 controls) and 24 ET brains, we also sequenced all GBA exons to evaluate genetic variation and frequency of GBA mutations in ET. Unique features of the study included (1) the evaluation of GBA mutation status, (2) case–control association analysis of LRRK2 SNPs in addition to evaluation of the frequency of LRRK2 mutations located in exons encoding the kinase, leucine rich repeat and Ras domains, (3) stratification of ET cases based on presence of rest tremor on examination (a parkin-sonian feature), and (4) analysis of ET brains, including several that were known to have Lewy bodies on post-mortem examination.