Table 2.
Results of case-control association studies and case-only studies of possible candidate genes for ET.
| Country | Gene | Chromosome | MIM/ Gene ID |
Allelic Variant/ Mutations |
Study Participants | Main Results | [Ref] |
|---|---|---|---|---|---|---|---|
| Spain | Cytochrome P450 family 2 subfamily D member 6 (CYP2D6) | 22q13.2 | 124030/1565 | CYP2D6 other than *1 (wild type) | 91 ET patients and 258 controls | Lack of association with ET | [129] |
| United States of America | Synuclein alpha (SNCA, PARK1) | 4q22.1 | 163890/6622 | 257, 259, 261, and 263 bp alleles of non-amyloid component of plaques (NACP-Rep1, promoter region) | 46 ET patients and 100 controls |
Association between allele 263 bp and risk for ET, with an OR (95% CI) = 6.42 (2.04–21.4) | [130] |
| Italy | Synuclein alpha (SNCA, PARK1) | 4q22.1 | 163890/6622 | Several SNPs (intronic region between exons 1 and 2, NACP-Rep1) | 106 ET patients and 90 controls | Lack of association with ET | [131] |
| United States of America | Synuclein alpha (SNCA, PARK1) | 4q22.1 | 163890/6622 | 20 variants in the SNCA locus | 661 ET patients and 1316 controls | Lack of association with ET | [132] |
| Italy | Parkin RBR E3 ubiquitin protein ligase (PRKN, PARK2) | 6q26 | 602544/5071 | Point mutations in the coding region of the gene | 110 ET patients | Detection of 2 previously reported polymorphisms and 4 novel rare variants located within exonic regions, and 4 new polymorphisms and 1 rare variant within intronic regions, but all of them were not causative | [133] |
| Turkey | Methyl-tetrahydrofolate reductase (MTFHR) | 1p36.22 | 607093/4524 | rs1801133 rs1801131 |
158 ET patients and 246 controls | Individuals with T677T or T677T/A1298A genotypes have even greater susceptibility to essential tremor. Nevertheless, individuals with C677C/A1298A and C677T/ A1298A genotypes had a protective effect on essential tremor. Individuals with T677T or T677T/A1298A genotypes have even greater susceptibility to essential tremor. Nevertheless, individuals with C677C/A1298A and C677T/ A1298A genotypes had a protective effect on essential tremor. Increased risk for ET in carriers of the T677T or T677T/A1298A genotypes and decreased risk in those with C677C/A1298A and C677T/A1298A genotypes |
[134,135] |
| China | Methyl-tetrahydrofolate reductase (MTFHR) | 1p36.22 | 607093/4524 | rs1801133 rs1801131 |
200 ET patients and 430 controls (Chinese Han) | Lack of association with ET | [135] |
| China | Alpha2-macroglobulin (A2M) | 12p13.31 | 103950/2 | A2M1000G (rs669) | 73 ET patients and 100 controls | Lack of association with ET | [136] |
| Spain | Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) | 10q23.33 | 124020/1557 | CYP2C19 *1, *2, and *3 | 200 ET patients and 300 controls | Association of genotype CYP2C19*1/CYP2C19*2 and allelic variant CYP2C19*2 with ET risk. Lack of association with adverse effect by primidone | [137] |
| United States of America | Leucine-rich repeat kinase 2 (LRRK2, dardarin, PARK8) | 12q12 | 609007/120892 | G2019S (rs34637584), I2012T (rs34015634), and I2020T mutations in the MAPKKK domain (exon 41) | 272 ET patients | Lack of detection of mutations | [138] |
| Singapore | Leucine-rich repeat kinase 2 (LRRK2, dardarin, PARK8) | 12q12 | 609007/120892 | Gly2385Arg (rs34778348) | 172 ET patients and 247 controls | Lack of association with ET (frequency of minor allele 2.9% vs. 4.0%) | [139] |
| Italy | Leucine-rich repeat kinase 2 (LRRK2, dardarin, PARK8) | 12q12 | 609007/120892 | G2019S (rs34637584), I2012T (rs34015634), and I2020T mutations in the MAPKKK domain (exon 41) | 116 patients with familial ET | Lack of detection of mutations | [140] |
| United States of America | Leucine-rich repeat kinase 2 (LRRK2, dardarin, PARK8) | 12q12 | 609007/120892 | 4 LRRK2 mutations (G2019S (rs34637584), I2020T, R1441C (rs33939927), and Y1699C), 2 rare LRRK2 variants (L1114L and I1122V), and 19 LRRK2 SNPs | 275 ET patients and 289 controls | Lack of association with ET | [141] |
| Singapore | Leucine-rich repeat kinase 2 (LRRK2, dardarin, PARK8) | 12q12 | 609007/120892 | R1628P (rs33949390) variant | 450 ET patients and 827 controls | Association of the R1628P variant with the risk for ET, with an OR (95% CI) = 2.20 (1.30–3.73) | [142] |
| Singapore | Leucine-rich repeat kinase 2 (LRRK2, dardarin, PARK8) | 12q12 | 609007/120892 | R1398 H (rs7133914) and N551K (rs7308720) variants | 518 ET patients and 2680 controls | Non-significant trend towards association with the risk for ET. OR (95% CI) = 0.71–1.17 for R1398H, and 0.89 (0.69–1.15) for N551K | [143] |
| China | Leucine-rich repeat kinase 2 (LRRK2, dardarin, PARK8) | 12q12 | 609007/120892 | rs34594498, rs34410987, and rs33949390 | 200 ET patients and 434 controls (Chinese Han) | Lack of association with ET | [144] |
| China | Leucine-rich repeat kinase 1 gene (LRRK1) | 15q26.3 | 610986/79705 | rs2924835 | 200 ET patients and 434 controls (Chinese Han) | Lack of association with ET | [144] |
| Spain |
CYP2C9
CYP2C8 |
10.q24 10q23.3 |
601130/− 601129/− |
CYP2C9*2 and *3 CYP2C8 *3 |
200 ET patients and 300 controls |
1.6-fold reduction in the frequency for CYP2C8*3 (p = 0.006), 1.35-fold reduction of CYP2C9*2 (p = 0.05). 1.52-fold reduction in the frequency for CYP2C9*3 (p = 0.07), and 1.33 fold reduction of frequency of at least one defective allele in ET patients (p = 0.002). Reduction in the percentage for carriers of the haplotype CYP2C8*3 * CYP2C9*2 in ET patients, p = 0.0001 as compared to controls. |
[145] |
| Spain | Alcohol dehydrogenase 1B (ADH1B) | 4q23 | 103720/125 | ADH2 *2 (rs1229984) | 204 ET patients and 200 controls | Lack of association with ET | [146] |
| China | Alcohol dehydrogenase 1B (ADH1B) | 4q23 | 103720/125 | rs6413413 rs1229984 |
200 ET patients and 229 controls | Lack of association with ET | [147] |
| Spain | Glutathione transferase Pi 1 (GSTP1) | 11q13.2 | 134660/2950 | GSTP1 Ile105Val (rs1695) | 200 ET patients and 220 controls | Lack of association with ET, with the exception of a significantly higher frequency of mutated allelic variants in ET patients exposed to pesticides than in non-exposed. | [148] |
| Spain | Histamine-N-methyl-transferase (HNMT) | 2q22.1 | 605238/3176 |
HNMT Thr105Ile (rs11558538) |
204 ET patients and 295 controls | Association between homozygous HNMT rs511558538 genotypes leading to high metabolic activity (p < 0.015), and the risk for ET (specially for late-onset ET) | [149] |
| United States of America | Histamine-N-methyl-transferase (HNMT) | 2q22.1 | 605238/3176 |
HNMT Thr105Ile (rs11558538) |
338 ET patients and 409 controls | Lack of association with ET | [150] |
| Spain | Paraoxonase 1 (PON1) | 7q21.3 | 168820/5444 |
PON1 Leu55Met (rs854560) PON1 Gln192Arg (rs662) |
201 ET patients and 220 controls | Lack of association with ET | [151] |
| United States of America | Glucosylceranidase beta (GBA) | 1q22 | 606463/2629 | GBA gene mutations | 93 ET patients and 62 controls (all Ashkenazi Jewish) | GBA mutations present in 7.5% (7/93) of ET patients and cases and 4.8% (3/62) of controls. Identification of 4 different heterozygous mutations (3 previously reported mutations— N370S, R496H, E326K—and 1 new missense variant—R44C). | [141] |
| China | Glucocerebrosidase (GBA) | 1q22 | 606463/2629 | L444P mutation | 109 ET patients and 657 controls | Lack of association with ET (0 ET patients and 1 control have heterozygote mutation) | [152] |
| United States of America | Microtubule-associated protein tau (MAPT) | 17q21.31 | 157140/4137 | rs1052553rs242557 | 356 ET patients and 409 controls |
Association between rs1052553G allele and risk for ET with an OR (95% CI) = 1.32 (1.03–1.67) Lack of association between rs242557 and risk for ET |
[153] |
| Spain | Microtubule-associated protein tau (MAPT) | 17q21.31 | 157140/4137 | rs1052553 | 200 ET patients and 291 controls | Lack of association with ET in this study and in the pooled data with those of another study [153] | [154] |
| Spain | Microtubule-associated protein tau (MAPT) | 17q21.31 | 157140/4137 | rs1052553 | 45 ET patients and 13 subjects without tremor from 11 families with ET and 308 controls | Increased frequency of rs1052553AA genotype and rs1052553A allele in ET patients compared with controls, but lack of association of this allele with the risk for ET in family-based association test | [52] |
| Canada and United States of America | Vacuolar protein sorting 35 homolog retromer complex component (VPS35, PARK17) | 16q11.2 | 601501/55737 | c.1858G > A (rs188286943) | 571 ET patients | Presence of the variant studied in 2 of 571 patients | [155] |
| Canada and United States of America | DnaJ (Hsp40) homolog, subfamily C, member 13 (DNAJC13, PARK21) | 3q22.1 | 614334/23317 | Asn855Ser (rs387907571) | 571 ET patients | Lack of association with ET | [155] |
| Spain, Italy, Germany, North America, and Taiwan | Triggering receptor expressed on myeloide cells 2 (TREM2) | 6p21.1 | 605086/54209 | Arg47Leu (rs75932628) | 1753 ET patients and 4164 controls (456 ET/2715 controls from Spain; 897 ET/1449 controls from other populations) | Increased risk for ET in carriers of the variant in the Spanish cohort, with an OR (95% CI) = 5.97 (1.203–29.626), but lack of association in the cohort of other populations | [156] |
| Spain | Heme-oxygenase 1 (HMOX1) | 22q12.3 | 141250/3162 | rs2071746 rs2071747 Copy number variations (CNV) |
202 patients with familial ET and 747 controls | Decreased risk for ET in carriers of rs2071746T allele | [157] |
| China | Heme-oxygenase 1 (HMOX1) | 22q12.3 | 141250/3162 | rs2071746 | 200 ET patients and 229 controls | Lack of association with ET | [147] |
| Spain | Heme-oxygenase 2 (HMOX2) | 16p13.3 | 141251/3163 | rs2270363 rs1051308 Copy number variations (CNV) |
202 patients with familial ET, and 747 controls | Decreased risk for ET in carriers of rs1051308G allele | [157] |
| China | Heme-oxygenase 2 (HMOX2) | 16p13.3 | 141251/3163 | rs4786504 rs1051308 |
200 ET patients and 229 controls | Lack of association with ET | [147] |
| Iran | Ras like without CAAX 2 (RIT2) | 18q12.3 | 609592/6014 | rs12456492 rs16976358 |
350 ET patients and 1000 controls | Association between rs12456492 and risk for ET in additive and in recessive models, with OR (95% CI) 1.37 (1.11–1.70) and 2.21 (1.47–3.30), respectively | [158] |
| China | Fibroblast growth factor 20 (FGF20) | 8p22 | 605558/26281 | rs1721100 rs1989754 rs10089600 rs12720208 rs17550360 |
200 ET patients and 426 controls (Chinese Han) | Lack of association with ET | [159] |
| China | Paired-like homeo-domain 3 (PITX3) | 10q24.32 | 602669/5309 | rs3758549 rs4919621 |
200 ET patients and 426 controls (Chinese Han) | Lack of association with ET | [160] |
| China | Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2, PARK22) | 7p11.22 | 616244/51142 | 182C>T (Thr61Ile) | 171 familial ET patients and 211 controls (Chinese Han) | Lack of detection of mutations in patients and controls | [161] |
| China | Transmembrane protein 230 (TMEM230) | 20p13-p12.3 | 617019/29058 | Stop codon TAG | 200 ET patients (100 with positive family history) and 400 controls | Lack of detection of mutations in patients and controls | [162] |
| Turkey | Vitamin D3 receptor (VDR) | 12q.13.11 | 601769/7421 | rs2228570 | 239 ET patients and 239 controls | Increased risk for ET in carriers of the rs2228570C (major) allele with an OR (95% CI) = 2.207 (1.051–4.636) | [163] |
| China | Vitamin D3 receptor (VDR) | 12q.13.11 | 601769/7421 | rs731236 | 200 ET patients and 229 controls | Lack of association with ET | [147] |
| China | Interleukin 17 alpha (IL17A) | 6p12.2 | 603149/3605 | rs8193036 | 200 ET patients and 229 controls | Lack of association with ET | [147] |
| China | Interleukin 1-beta (IL1B) | 2q14.1 | 147720/3553 | rs1143633, rs1143643, rs1143634 | 200 ET patients and 229 controls |
Association between rs1143633 allele and the risk for ET, with an OR (95% CI) = 2.57 (1.38–4.81) | [147] |
| China | Nitric oxide synthase 1 (NOS1) | 12q24.22 | 163731/4842 | rs693534, rs7977109 | 200 ET patients and 229 controls | Lack of association with ET | [147] |
| China | NUS1 dehydrodoli-chyl diphosphate synthase subunit (NUS1) | 6q22.1 | 610463/116150 | Sequencing of the 5 coding regions and the exon-intron boundaries of the gene | 395 ET patients and 395 controls | Lack of association with ET | [164] |
OR: odds ratio (OR); 95% CI: 95% confidence intervals (CI); NAD: non-available data.