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Keywords:

  • essential tremor;
  • genetics;
  • family history;
  • linkage studies;
  • genetic polymorphisms

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Despite the research, few advances in the etiopathogenesis on essential tremor (ET) have been made to date. The high frequency of positive family history of ET and the observed high concordance rates in monozygotic compared with dizygotic twins support a major role of genetic factors in the development of ET. In addition, a possible role of environmental factors has been suggested in the etiology of ET (at least in non-familial forms). Although several gene variants in the LINGO1 gene may increase the risk of ET, to date no causative mutated genes have been identified. In this review, we summarize the studies performed on families with tremor, twin studies, linkage studies, case–control association studies, and exome sequencing in familial ET.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Essential tremor (ET) is characterized by postural or kinetic tremor at 4–12 Hz involving mainly upper extremities, although it can also spread to the head, voice, tongue, chin, and other body parts. Despite the fact that ET is one of the most frequent movement disorders, its etiology is still unknown. Although the frequency of family history of tremor in patients with ET is high (50–60%), a role of certain environmental factors in the etiology of ET, at least in non-familial forms, has been suggested [1-4]. The aim of this review is to revise the literature on all aspects related to genetics of ET by summarizing reports on the family history of tremor, twin studies, linkage studies, as well as genome-wide association studies (GWAS), case–control association studies, and exome sequencing studies in ET.

Studies assessing frequency of family history of tremor in essential tremor patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

The heritability of ET is a known fact since the beginning of the 19th century. The frequency of positive family history of tremor among subjects with ET is variable [5-26], ranging over different series from 17.4% [5] to 100% [6]. The wide variability found in the familial aggregation of tremor could be due to biases derived from methodological differences between studies:

  1. Some studies (Table 1) involved patients with ET who sought specialized attention for ET (in general, the more severely affected are more prone to recognize the presence of tremor in their relatives; therefore, they may not be representative of all ET cases), while others included population survey cases (Table 1). In fact, Louis et al. [27] reported a frequency of family history of tremor 4.7 times higher in patients with ET who sought attention in specialized units than that obtained in community surveys.
  2. In many of these studies, the relatives of patients with ET were not examined, and this fact could be related with an underestimation of the real frequency of family history of tremor. This issue was confirmed by Busenbark et al. [23] by mailing structured questionnaires which reported tremor in 67.7% of the first-degree relatives of patients with ET, a percentage which increased to 96% when the relatives underwent a neurologic exam. Louis et al. [28], after examining 160 relatives of patients with ET, found that 7.5% fulfilled diagnostic criteria for definite or probable ET, whereas only 1.25% could have been diagnosed with ET according to the family reports obtained on the presence or absence of tremor in their relatives. In addition, Prakash and Tan [29] reported low sensitivity (43.3%), although a high specificity (94.4%), of family history data provided by patients with ET, and a tendency in which the relatives with more severe tremor were more easily recognized as having ET by the affected patients with ET.
Table 1. Studies assessing the frequency of positive family history of tremor or essential tremor (ET) (at least one other relative affected) in patients with ET
Authors, year (Reference)Method% of patients with positive family history
Kulcke, 1904 [5]Hospital-based survey17.4
Larson and Sjögren, 1960 [6]Population survey100
Critchley, 1972 [7]Hospital-based survey38.1
Sutherland et al., 1975 [8]Hospital-based survey62.5
Hornabrook and Nagurney, 1976 [9]Population survey18.0
Rautakorpi, 1978 [10]Population survey70.0
Gerstenbrand et al., 1982 [11]Hospital-based survey71.7
Rajput et al., 1984 [12]Hospital-based survey38.7
Aiyesimoju et al., 1984 [13]Hospital-based survey60.0
Martinelli et al., 1987 [14]Hospital-based survey43.2
Taddei and Ludin, 1988 [15]Hospital-based survey61.0
Mengano et al.,1989 [16]Hospital-based survey75.4
Hsu et al., 1990 [17]Hospital-based survey32.0
Lou and Jankovic, 1991[18]Hospital-based survey62.6
Pereira et al., 1993 [19]Hospital-based survey37.7
Salemi et al., 1994 [20]Population survey35.5
Borges et al., 1994 [21]Hospital-based survey47.2
Koller et al., 1994 [22]Hospital-based survey63.7
Busenbark et al., 1996 [23]Hospital-based survey96.0
Tallón-Barranco et al., 1998 [24]Hospital-based survey46.8
Benito-León et al., 2003 [25]Door-to.door population survey34.0
Whaley et al., 2007 [26]Hospital-based survey50.0
Jiménez-Jiménez et al., 2007 [4]Case–control hospital-based study66.2

Finally, in a study of 20 families with ET, Bain et al. [30] reported definite ET, based on examination, in 53 of 131 relatives (40.5%; 93 first-degree and 38 more distant relatives) of 20 index patients with hereditary ET.

In summary, despite the aforementioned methodological differences, studies assessing the frequency of family history of tremor in ET patients suggest a high heritability of this disorder. The role of direct examination of patients and relatives should be considered as very important in determining the real prevalence of family history of tremor.

Studies assessing the frequency of family history of tremor in essential tremor patients and controls

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Two case–control studies by our group (both hospital-based) found that ET subjects had a more frequent family history of tremor (46.8–66.2%) than healthy subjects (6.2–6.3%) [4, 24]. The assessment of positive family history of tremor (at least one relative affected) was carried out through personal interviews with patients or controls, but the relatives were not examined.

Jankovic et al. [31] reported the presence of tremor in 23.4% of relatives of patients with ET, while the frequency of tremor in relatives of control subjects was 2.2% (they examined patients with ET and controls, and both groups were questioned about the presence, location, and nature of tremor in their relatives).

Louis et al. [32], in a study including 59 patients with ET, 72 controls, 234 relatives of patients with ET and 226 relatives of healthy controls (all of them underwent a standardized tremor examination), found ET in 22.5% of first-degree relatives of patients with ET and in 5.6% of first-degree relatives of controls (relative risk = 4.67, 95% confidence interval = 1.90–11.49, P = 0.0008). In addition, the relative risk (RR) was higher in relatives of cases with earlier onset (≤50 years) than in those with later onset (RR = 10.38 vs 4.82).

Louis et al. [33] found a frequency of 8.6% of ‘asymptomatic’ tremor in ET relatives. In a study involving subjects with mild tremor who did not fulfill diagnostic criteria for ET, the score obtained on a clinical scale of tremor when the subjects were relatives of patients with ET was significantly higher than with the controls' relatives, suggesting the occurrence of an ET inheritance factor with incomplete penetrance [34].

Despite the methodological differences between studies assessing the frequency of family history of tremor in patients with ET and controls, positive family history is clearly more frequent in patients with ET [4, 24, 31, 32]. However, the correct approach in the assessment should be the clinical examination of the index patients and controls and their respective relatives, as was demonstrated in one of these studies [33].

Inheritance patterns in families with essential tremor

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

The inheritance pattern of ET is unclear. Despite reports of several ET families with typical autosomal dominant inheritance [6, 30, 35-39], the frequency of affected first-degree relatives reported in some studies is approximately 23% [31, 32], much lower than the 50% expected for autosomal dominant inheritance with complete penetrance and slightly lower than the 25% expected for autosomal recessive inheritance. These data suggest that ET can be caused by an autosomal dominant gene with low penetrance.

The possibility of a multifactorial inheritance pattern, that is, the result of interplay between more than one gene and environmental factors should be also taken into account. Diseases with multifactorial inheritance can be caused by the sum of some genetic and environmental factors. The possible genetic causes of non-familial, ‘sporadic’, or genetically complex ET could be explained by a complex inheritance pattern. In addition, the possibility of autosomal recessive and X-linked patterns of inheritance cannot be excluded [40, 41].

Ma et al. [42], evaluating 91 family members from four multigenerational ET families, found 64 subjects fulfilling diagnostic criteria for definite ET, and the percentage of affected offspring in each generation was between 75 and 90%, higher than the 50% expected for a standard dominant inheritance pattern, suggesting the possibility of a non-Mendelian pattern of inheritance or ET in some pedigrees.

We suggest that mitochondrial DNA mutations are not a main cause of familial tremor because ET can be inherited both through maternal and paternal lines. In a clinical study, our group reported bilinear transmission (that is, history of tremor in both parents) in 5.4% of patients with ET, and a higher trend toward maternal transmission in females than in males [24]. Rajput and Rajput [43] described, in two families in which both parents and one of their sons suffered from ET, earlier onset and higher severity of tremor in the sons than in the parents, and they suggested a genetic basis of the phenotypic expression of ET.

The possible presence of phenocopies in families with ET [41, 44] must be taken into account. This term defines individuals with a similar phenotype, which can be caused by different genetic or environmental determinants. The occurrence of phenocopies is frequent in common diseases such as ET and can be explained by chance [44]. In an attempt to provide answers to the presence of phenocopies in families with ET and to explain the non-Mendelian features in the genetics of this disease, Zimprich [44] suggested the hypothesis of a possible role of epigenetic factors (heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence or functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence) in the inheritance of ET.

‘Genetic anticipation’ in essential tremor

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Genetic anticipation is a phenomenon, whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase in severity of symptoms is also noted. Although genetic anticipation could be related with different types of inheritance, it is more often reported with autosomal dominant diseases, such as Huntington's disease, myotonic dystrophy, or several spinal cerebellar ataxias. Critchley [35], after analyzing the family trees which contained sufficient data of his own patients and of several reports diagnosed with ET, suggested the presence of genetic anticipation in this disease. Other authors have described genetic anticipation in families with autosomal dominant ET [39], and several studies have found genetic anticipation of tremor among patients with positive family history of tremor [4, 6, 10, 12, 22, 24, 45, 46]. The two ET families with bilineal transmission described by Rajput and Rajput [43] also showed genetic anticipation. However, no repeat mutations have been clearly associated with familial ET.

Twin studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Twin concordance means a higher than expected frequency of the same trait in both twins. A concordance rate of a trait, which is higher in monozygotic than in dizygotic twins, supports a role of genetic factors. To date, only two studies have analyzed the concordance rates of ET between twins.

Tanner et al. [47] identified 196 twins with postural or kinetic tremor. After excluding subjects with Parkinson's disease (PD) and subjects with missing data, sixteen twin pairs were both affected with ET. Concordance rates reported in this study were 0.60 for monozygotic and 0.27 for dizygotic twins.

Lorenz et al. [48], in a screening of 2448 twins of the Danish Twin Registry aged 70 years or more, registered 162 twin pairs with a positive screening test for ET in at least one of the twins. They examined 109 of them: thirty-six twins fulfilled the Tremor Investigation Group (TRIG) criteria for definite or probable ET, and the concordance rates were 0.93 for monozygotic and 0.29 for dizygotic twins. The authors concluded that these data suggest that a disease phenotype consisting of definite and probable ET is considered appropriate phenotype with high heritability to be used in linkage studies.

The existence of orthostatic tremor [49, 50] and isolated voice tremor [51] has been described in monozygotic twins as anecdotal reports.

Linkage studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Linkage studies look at physical segments of the genome that are associated with given traits. Linkage studies in families with ‘pure’ monogenic ET identified three susceptibility loci for familial ET mapped at chromosomes 3q13 [52], 2p25-p22 [53], and 6p23 [54], although the responsible genes have not been clearly identified.

ETM1 (chromosome 3q13, OMIM 190300)

The first chromosomal region linked to ET was mapped in a genome-wide scan study involving 16 Icelandic families, which included 75 affected individuals with ET in an autosomal dominant pattern [52]. This gene was named FET1 (familial ET) or ETM1 (OMIM 190300) and was mapped at chromosome 3q13 with a genome-wide significance when the data were analyzed either parametrically, assuming an autosomal dominant model (LOD score = 3.71), or nonparametrically (LOD score = 4.70). However, the families involved in the study were very small, and the highest single-family LOD score was 1.29, far below the threshold for reliably mapping a monogenic disorder (at least equal to 3.00), so these results have to be taken cautiously.

In addition, other authors did not find linkage to ETM1 in a large family with autosomal dominant ET involving six generations [38], in 11 Slavonic and 19 Tajik families [55], in a fifth-generation Italian kindred with autosomal dominant ET [56], and in four large ET Italian families, comprising 29 affected individuals [57].

Among the variants located in the ETM1 locus, SNP312G > A (rs6280) in the dopamine receptor D3 (DRD3) gene (OMIM 126451), resulting in a non-synonymous Ser9Gly amino acid change, has been proposed as a risk ET variant. Lucotte et al. [58] found association of DRD3Gly in 23 of 30 French families with ET, and between DRD3Gly/Gly genotype with an earlier age at onset of tremor. The association of the DRD3Gly allele with both risk and an earlier age-onset of ET was also found in two replication studies in North American (276 subjects with ET and 184 healthy controls) [59] and in Spanish populations (201 subjects with ET and 184 healthy controls). This association was not replicated in other populations [61-64] and did not segregate with ET in large families [42]. A meta-analysis including the data from our study and of those published previously show increased risk of DRD3Gly for ET [60]. Another study published after this meta-analysis found opposite results [65]. Considering all these studies, a non-significant trend toward an overrepresentation of the DRD3Gly allele in ET compared with controls can be calculated (Table 2).

Table 2. Results of genome-wide association studies (GWAS) and case–control association studies of possible candidate genes for essential tremor (ET)
RelationGeneChromosomeOMIMReferencesAllelic variantTotal patients with ET N (frequency)Controls N (frequency)OR (95% CI)P-value
  1. OR, odds-ratio; 95% CI, 95% confidence intervals; NAD, non-available data.

  2. a

    Patients with family history of ET.

  3. b

    Patients with definite ET.

ETM1 DRD3 3q13126451 [58-65] DRD3Gly (rs6280)1426 (0.340)1631 (0.308)1.16 (0.99–1.35)0.057
ETM2 HS1BP3 2p24.1609359 [73] HS1BP3Gly (rs11680700)222 (0.045)132 (0.045)0.89 (0.91–1.92)0.980
GWAS LINGO1 15q24.3609791 [76, 83-92] rs9652490G3972 (0.237)20714 (0.223)1.17 (1.00–1.36)0.069
    [83, 85, 87, 89-92] rs9652490G a906 (0.231)3549 (0.195)1.27 (1.03–1.57)0.014
    [76, 85, 87, 88, 90-92] rs11856808T2076 (0.371)18792 (0.344)1.20 (1.05–1.36)0.016
    [85, 87, 90-92] rs11856808Ta720 (0.346)2565 (0.304)1.21 (1.01–1.44)0.031
SLC1A2 11p13p12600330 [77] rs3794087T658 (0.311) b1490 (0.221)1.59 (1.36–1.84)3.44 × 10−10
Posible candidate genes for Parkinson's disease MAPT 17q21.1157140 [110, 111] rs1052553G539 (0.235)697 (0.256)0.89 (0.74–1.08)0.221
Histamine-N-methyl-transferase (HNMT) 2q22.1605238 [112, 113]

HNMT105Thr

(rs511558538)

542 (0.908)704 (0.889)1.23 (0.83–1.81)0.285
CYP2D6 22q13.1124030 [114] CYP2D6 other than a1 (wild type)91 (0.231)258 (0.213)1.11 (0.60–2.03)0.727
Methyl-tetrahydrofolate reductase (MTFHR) 1p36.3607093 [115]

MTFH677C

MTFHR1298C

158 (0.358)

158 (0.339)

246 (0.301)

246 (0.264)

1.31 (0.84–2.05)

1.45 (0.92–2.28)

0.210

0.096

Alpha2-macroglobulin (A2M) 12p13.31103950 [116] A2M1000G 73 (NAD)100 (NAD)NAD>0.05
CYP2C19 10q24.1-q24.3124120 [117] CYP2C19 a2 and a3200 (0.16)300 (0.11)1.54 (0.89–2.68)0.104

CYP2C9

CYP2C8

10.q24

10q23.3

601130

601129

[118]

CYP2C9 a2 and a3

CYP2C8 a3

200 (0.198)

200 (0.108)

300 (0.287)

300 (0.170)

0.65 (0.42–1.03)

0.60 (0.34–1.06)

0.051

0.063

Alcohol dehydrogenase 2 (ADH2) 4q22103720 [119] ADH2 a2204 (0.052)200 (0.068)0.76 (0.31–1.83)0.355
Glutathione transferase P1 (GSTP1) 11q13134660 [120] GSTPVal 200 (0.315)220 (0.309)1.03 (0.67–1.59)0.854
Paraoxonase 1 (PON1) 7q21.3168820 [121]

PON1 55Met

PON1 192Arg

201 (0.587)

201 (0.301)

220 (0.614)

220 (0.302)

0.90 (0.68–1.18)

0.99 (0.74–1.33)

0.506

0.522

GABA receptor (GABR) genes GABR Alpha1 (GABRA1) 5q34137160 [123] GABRA1 156C 121 (0.227)114 (0.228)0.97 (0.50–1.87)0.984
GABR Rho1 (GABRR1) 6q14-q21137161 [124]

GABRR1 26 V

GABRR1 27R

200 (0.313)

200 (0.060)

250 (0.288)

250 (0.046)

1.12 (0.84–1.50)

1.32 (0.74–2.37)

0.425

0.348

GABR Rho2 (GABRR2) 6q14-q21137162 [124] GABRR2 455M 200 (0.225)250 (0.192)1.22 (0.89–1.69)0.225
GABR Rho3 (GABRR3) 3q11.2 [124] GABRR3 205Y 200 (0.213)250 (0.234)0.88 (0.64–1.21)0.443
GABR Alpha4 (GABRA4) 4p12137141 [125] GABRRA4 26M 200 (0.343)250 (0.386)0.83 (0.63–1.09)0.179
GABR Epsilon (GABRE) Xq28300093 [125] GABRE 102S 200 (0.360)250 (0.336)1.11 (0.84–1.46)0.452
GABR Theta (GABRQ) Xq28300349 [125] GABRQ 4478F 200 (0.393)250 (0.390)1.01 (0.77–1.32)0.939
Exome sequencingFused in sarcoma/ translated in liposarcoma (FUS/TLS)16911.2137070 [141]

rs741810

rs1052352

rs2735393

rs4889537

259 (0.250)

259 (0.370)

259 (0.240)

259 (0.270)

262 (0.270)

262 (0.410)

262 (0.280)

262 (0.270)

0.91 (0.60–1.20)

0.86 (0.67–1.10)

0.84 (0.63–1.10)

0.83 (0.63–1.10)

0.50

0.23

0.21

0.20

ETM2 (chromosome 2p25-p22, OMIM 602134)

Higgins et al. [53] mapped the ETM2 locus (OMIM 602134) in a large American-Czech family with ‘pure’ autosomal dominant ET in the boundaries of D2S272 at chromosome 2p25-p22 (maximum LOD score = 5.92). The family included 138 members and 18 ET subjects who showed genetic anticipation over generations. They found a CAG repeat expansion among affected relatives, and it could not be determined whether it was located in the ETM2 locus. The same research group confirmed the presence of linkage in four independent American families with ET delimiting the disease haplotype between D2S224 and D2S405 [66]. The disease haplotype (D2S224-D2S2221) contains at least thirty-three transcripts, including five candidate ET genes (MATN3, LAPTM4A, SDC1, PUM2, and APOB) [67]. This group also performed case–control association studies on Asian and North American populations with some microsatellite markers at ETM2 in familial ET and found a statistically significant association in only one of them [68, 69].

Among the candidate genes included in the region, the Ala265Gly rs11680700 variant of HS1BP3 exon 7 (heat shock1-binding protein 3, OMIM 609359) was reported in two families with ET [70], and in 16.4% of 73 unrelated patients with familial ET, but in none of the 304 analyzed controls [70, 71]. However, in a study of two families with 27 affected members, only three subjects of one of the families carried this variant [72], and a case–control association study found lack of association between this variant and ET [73]. Kim et al. [74] reported that a decrease in the number of short tandem repeats within the ETM1234 microsatellite was more often observed among patients with ET than in controls in the Korean population.

Other authors found no linkage to ETM2 in a large family with autosomal dominant ET [38] in 11 Slavonic and 19 Tajik families [55], in a fifth-generation Italian kindred with autosomal dominant ET [56], and in four large ET Italian families, comprising 29 affected individuals [57]. Zahorakova et al. [75] found no association between the ETM1231, ETM1234, and ETM1240 markers located within the ETM2 locus in 61 Czech patients with familial ET compared with 68 healthy controls. Thus, the ETM2 responsible variant in familial ET remains unknown.

ETM3 (chromosome 6p23, OMIM 611456)

A genome-wide linkage study of seven large American families with ET comprising 325 individuals under an affected-only model (65 of them were affected by ‘definite ET’, and 15, belonging to three families, had concomitant dystonia), found linkage to chromosome 6p23 in only two families, whereas the others showed no evidence for linkage to the ETM3 locus [54]. Considering the two families, a maximum LOD score of 4.248 at D6S1630 and D6S1605 was found, although the main family 3/14 affected would certainly be phenocopies because they did not carry the disease haplotypes. Sequencing of 15 candidate genes located within the region found no sequence variants with pathogenic significance.

Aridon et al. [56] in a fifth-generation Italian kindred with autosomal dominant ET, and Novelletto et al. [57], in four large ET Italian families comprising 29 affected individuals, excluded linkage to markers in chromosome 6p.

Genome-wide association studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Genome-wide association studies consist of analyzing many common genetic variants in cases and controls to elucidate whether any SNP is associated with the disease trait. To date, there are two GWAS related with ET which found an association between two SNPs in the Leucine-rich repeat and Ig domain containing Nogo receptor interacting protein-1 gene (LINGO1) [76, 77], and an intronic variant in the solute carrier family 1- glial affinity glutamate transporter-, member 2 (SLC1A2) gene with ET [77].

LINGO1 gene

The first genome-wide association study performed on patients with ET [76] found a strong statistical association of rs9652490 and rs11856808 SNPs in the LINGO1 gene (OMIM 609791) and the risk of ET in an Icelandic population. However, only the association of rs9652490 with ET was confirmed in different populations, and the rs11856808 association disappeared after adjusting for the rs9652490 genetic effect [76]. LINGO1 is a transmembrane protein expressed in neural cells and oligodendrocytes that inhibits the differentiation of oligodendrocyte precursors into mature oligodendrocytes and interferes with myelination and remyelination neuronal processes [78, 79]. LINGO1 expression is increased in the substantia nigra of PD brains compared with controls, and dopaminergic neurons of LINGO1 knockout mice are protected against degeneration [80] LINGO1 gene shares structural properties with Leucine-Rich Repeat Kinase 2 gene (LRRK2) linked to familial PD [81, 82]. Thus, given the clinical and epidemiological overlap between these disorders, LINGO1 is an interesting candidate gene to modify risk of ET.

Since then, five studies have replicated the effect of rs9652490 on ET [83-87], whereas another five studies failed to confirm the association [88-92]. With regard to rs11856808, Thier et al. [85] replicated the association, while five other groups found no association [87, 88, 90-92]. A meta-analysis (which took into consideration the weight of each study, and the homogeneity between studies) found no association of the rs9652490G allele, and a weak association of the rs11856808T allele, with the risk of ET, although both variants showed a weak association with the risk of developing ET in patients with positive family history of ET [93] (Table 2).

To replicate the GWAS association findings, Vilariño-Güell et al. [84, 86] reported a significant association with ET between the LINGO1 rs9652490A/A genotype under a recessive model [OR = 0.63 (95% CI 0.42–0.95, P = 0.026)], and with the rs9652490A allele in a North American series. These results are in disagreement with those of other studies in which the association with ET was driven by the minor allele rs9652490 [76, 83] and could have affected meta-analysis studies [93]. As the authors state, the association of opposite alleles at the same biallelic locus can hypothetically occur when the two candidate alleles are in linkage disequilibrium with independent ancestral causative variants at the same locus [94].

Thier et al. [85] described an association between the rs8030859T allele and the risk of ET in the German population. Clark et al. [87] found a weak though significant association of the SNPs rs177008, rs12213467, and rs8028808, with early-onset ET (age at onset <40 years).

In addition, other authors have reported an association of five tagging SNPs of the LINGO1 and LINGO2 (OMIM 609793) genes (rs4885887, rs3144, rs8028808, and rs12905478, rs1412229) with the risk of developing ET [84, 86].

Finally, Wu et al. [95] described an association of the LINGO2 rs7033345C/C genotype and the LINGO2 rs10812774C allele with the risk of ET under a recessive model.

SLC1A2 gene

SLC1A2 gene (solute carrier family 1 – glial affinity glutamate transporter – member 2), also known as EATT2 or GLT-1, located at the chromosome 11p13-p12 (OMIM 600330) encodes a member of a family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors (Link http://www.ncbi.nlm.nih.gov/gene?term=scl1a2). Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis [96, 97].

A recent GWAS involving 990 patients with ET (658 of them with definite ET) and 1490 controls found that the SNP rs3794087 in the SLC1A2 gene was associated with the risk of developing definite ET, with an odds-ratio of 1.59 (1.36–1.84) (Table 2) [77]. Although the association of SLC1A2 variants with ET seemed promising, a replication study involving 202 ET patients with positive family history of ET and 308 healthy controls failed to show an association between SLC1A2 and the risk of ET, with an odds-ratio of 0.82 (0.60–1.12) (García-Martín E, Martínez C, Alonso-Navarro H, Benito-León J, Lorenzo-Betancor O, Pastor P, Ortega-Cubero S, López-Alburquerque T, Agúndez JAG, Jiménez-Jiménez FJ, unpublished data). Thus, the possible role of this gene should be assessed in further replication studies.

Studies on candidate genes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Given that postural and intention tremors are frequently observed in many neurological diseases, including PD, dystonia, and others, the hypothesis of common etiological factors has prompted some researchers to analyze genes related with some of these diseases in patients with ET compared with controls.

ET genetic studies on genes possibly related with Parkinson's disease

There are many clinical, epidemiologic, genetic, neuroimaging, and neuropathological data that suggest a relationship between PD and ET [98, 99]. For this reason, many of the candidate genes studied in patients with ET are related with monogenic familial PD or have shown an association with the risk of PD in case–control association studies (although this association was not always confirmed). Only three genes (of a total of 11) have been suggested as major contributors to the risk of PD by a meta-analysis of datasets from 5 GWAS from the USA and Europe [100]: alpha-synuclein (SNCA, OMIM 163890), LRRK2 (OMIM 609007), and microtubule associated protein tau (MAPT; OMIM 157140) genes.

The studies on genes associated with familial PD in patients with ET include the following:

  1. Tan et al. [101] reported an overrepresentation of the NACP-Rep1 polymorphic allele, located 10 kb upstream of the SNCA gene, in sporadic ET and PD, suggesting an etiologic link between these two disorders. However, two further studies of cases and controls [102, 103] failed to confirm the association of SNCA gene polymorphisms with the risk of ET.
  2. Pigullo et al. [104] failed to identify parkin gene mutations among 110 unrelated ET subjects.
  3. Several studies, in different populations, did not show any association between the most common mutations in the LRRK2 gene and ET [105-108].
  4. Clark et al. [108] found a prevalence of mutations of the glucocerebrosidase gene (GBA) (OMIM 606463) in Ashkenazi Jewish patients with ET similar to that in Ashkenazi Jewish controls, suggesting that changes in this gene are probably not a common cause of ET in this population. Sun et al. [109] did identify a GBA gene L144P mutation in 1 of 659 controls but in none of 109 ET Chinese patients.

A recent study found a weak association of the rs1052553 MAPT H1/H2 discriminating SNP with ET, but failed to confirm an association of the H1c subhaplotype (SNP rs242557) with the risk of ET [110]. A recent study by our group and the analysis of the pooled data of both studies showed no association between the rs1052553 SNP and the risk of ET [111] (Table 2).

The results of case–control association studies in ET involving other genes that had been previously studied in patients with PD by some investigators are summarized in Table 2. In summary, the results of initial studies have never been consistently confirmed by others or replication studies have not yet been displayed.

ET genetic studies on other candidate genes

A possible role of genes related with gamma-aminobutyric acid (GABA) transmission in the risk of ET was first suggested by the report by Kralic et al. [122] of an experimental model of ET, resembling human ET (characterized by postural and kinetic tremor and motor incoordination), using a knockout GABAA receptor alpha1 subunit (GABRA1; chromosome 5q34; OMIM 137160) mice. However, no change in the risk of ET has been found after analyzing most of the GABA receptor genes (GABR) [123-126] including GABRA1 [123], or GABA transporter genes [126] (Table 2).

Louis et al. [127] found an increased risk of ET as a result of the interaction between high serum lead concentrations and the ALAD-2 allele of delta-amino-levulinic acid dehydratase gene (ALAD; chromosome 9q32; OMIM 125270).

Negative association data from studies of other possible candidate genes for ET risk are summarized in Table 3.

Table 3. Data from other studies of possible candidate genes for essential tremor (ET)
GeneChromosomeOMIMReferencesRationaleFindings
Torsin 1A, Tor1A or DYT1 9q4.11605204 [55, 128, 129] Postural tremor is a frequent clinical feature of idiopathic torsion dystoniaNo association with ET
Spinocerebellar ataxia 12 (SCA12) 5q31-q33604236 [130] Action tremor of the head and arms is very often present in early stages of SCA12None of 30 patients with ET presented a CAG repeat larger than 19

Spinocerebellar ataxia 3 (SCA3)

Spinocerebellar ataxia 2 (SCA2)

14q32.12

12q24

109150

183090

SCA3 can present initially with ET symptomsSCA3 mutations were present in 1 patients with ET, and SCA2 in none of the 177 patients with ET analyzed
Fragile X-associated tremor/ataxia syndrome (FXTAS, FMR1 gene) Xq27.3309550 Anecdotal reports of patients with ET carrying a fragile X permutation [127, 128]No association in 3 large series of patients with ET and controls [134-136]
Potassium Channel, Calcium-activate, intermediate/small conductance, subfamily N, member 3 (KCCN3 or SKCA3) 1q21.3602983 [137] Some studies linked this gene with the risk of schizophrenia (not confirmed in others) and with juvenile myoclonic epilepsyNo CAG expansions of this gene in a large cohort of Italian patients with ET
Calcium Channel, Voltage-dependent, P/Q type, Alpha-1A subunit (CACNA1A or CACNA1A4) 19p13.2601011 [137] Relation with episodic ataxia, type 2, migraine familial hemiplegic, and spinocerebellar ataxia 6No CAG expansions of this gene in a large cohort of Italian patients with ET
Sodium Channel, Voltage-gated, Type VIII, Alpha subunit (SNCA8 or NAV1.6) 12q13.13600702 [138] Mutations in this gene cause congenital tremor in mice.No mutations in this gene in 95 patients with autosomal dominant ET
Mitochondrial genes   [139] Association of alterations in mitochondrial genes with some neurodegenerative diseases.Deletions in 16S rRNA, ND1 and ND2, in the complex I region, CO II at the complex IV, ATPase DT6/8 at the complex V, and in some coding regions of complex III, found in 9 patients with ET and absent in 6 healthy controls.

Exome sequencing studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

Whole exome sequencing is an efficient strategy to selectively sequence the coding regions of the genome. The first whole exome sequencing published in familial ET identified a p.Q290X mutation in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene (which is mutated in families with amyotrophic lateral sclerosis and frontotemporal lobar degeneration) as the cause of ET in a large ET-affected Canadian family. Further screening of 270 ET cases identified two rare missense FUS variants [140]. However, Parmalee et al. [141] failed to find any FUS/TLS mutation in 116 early-onset ET cases or a significant association by genotyping four tagging SNPs in a case–control series (Table 2).

Conclusions and future directions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

The high frequency of family history of tremor found in patients with ET, especially in the studies where the relatives of patients were examined, data from family studies, and concordance rates which are higher in monozygotic than in dizygotic twins, support a role of inheritance in the etiology of ET. Despite the fact that some family reports suggest an autosomal dominant pattern of inheritance, there have been reports of some ET families with a higher frequency of relatives with ET than that expected for a typical autosomal dominant inheritance, suggesting a non-mendelian pattern. Other types of inheritance cannot be definitively excluded in some families.

Linkage studies have identified three genes/loci in a low number of families with apparently autosomal dominant ET (but not in many others), the responsible genes have not been identified, and they only explain a small percentage of ET heritability. The possible association of ET with genes mutated in other degenerative diseases such as idiopathic torsion dystonia, PD, SCAs, and others has not been found. Among the diverse case–control association studies, only some LINGO1 gene variants seem to modestly increase the risk of ET in patients with family history of this disease. The recent findings of SLC1A2 gene association and the role of FUS in familial ET needs further studies.

In summary, the researching difficulties in the identification of genetic determinants of ET, which remain unsolved, may be due to the following:

  1. The lack of a disease-specific marker for the diagnosis of ET (this is still based on clinical examination). Most series have collected only clinical criteria which are variable, and probably this is a major limitation to the results of different studies.
  2. The high frequency of overlap of ET with other disorders such as PD [97, 98] or dystonia [54] can make the diagnosis difficult.
  3. The high prevalence of ET, which increases with aging, may lead to the inclusion of phenocopies in genetic studies, and this fact can affect their final results.

To date, neither linkage studies, nor GWAS, nor case–control association studies of candidate genes have been able to conclusively identify any gene responsible for ET. We suggest that the ideal studies to address the genetics of ET should fulfill the following conditions:

  1. Index patients should be diagnosed with definite and ‘pure’ or ‘monosymptomatic’ ET according to standardized criteria [142] and with a family history of ET. Index patients could participate in both case–control association studies or in family studies. Healthy controls included in case–control studies must not have family history of tremor and should undergo a neurological examination to exclude ET.
  2. Ideally, at least all available first-degree relatives of each index patient should undergo a clinical examination including rating scales for tremor [143, 144]. The coexistence of other neurological diseases, such as PD or dystonia, in these relatives should not be an exclusion factor, although ET families should be divided into several subtypes (‘pure ET’, ‘ET-PD’, ‘ET-dystonia’), and these subtypes should be analyzed separately.
  3. Blood DNA should be obtained from patients and their relatives and from healthy controls for future genetic studies attempting to establish the role of genetic factors in the different subtypes of ET.
  4. A multicenter and prospective design with long-term follow-up to assess further development of PD or other associated disorders in the index patients, in their relatives, or both. In addition, a percentage of relatives of patients with ET without tremor in the initial assessment could develop ET during the follow-up period.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References

We are grateful to Professor James McCue for assistance in language editing. Research at authors' laboratories is financed by grants PS09/00943, PS09/00469, PI12/00241, PI12/00324, and RETICS RD12/0013/0002 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, SAF2006-10126 and SAF2010-22329-C02-01 from the Spanish Ministry of Science and Innovation and GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. Studies assessing frequency of family history of tremor in essential tremor patients
  6. Studies assessing the frequency of family history of tremor in essential tremor patients and controls
  7. Inheritance patterns in families with essential tremor
  8. ‘Genetic anticipation’ in essential tremor
  9. Twin studies
  10. Linkage studies
  11. Genome-wide association studies
  12. Studies on candidate genes
  13. Exome sequencing studies
  14. Conclusions and future directions
  15. Acknowledgements
  16. Conflicts of interest
  17. References