Genetics of Essential Tremor


The etiopathogenesis of essential tremor (ET) is not definitively resolved. The role of genetics in the development of ET is supported by epidemiological and family studies. A high frequency of positive family history of ET or tremor among subjects with ET has been reported. In addition, twin studies have shown higher concordance rates of ET in monozygotic than in dizygotic twins. However, a role of environmental factors, at least in nonfamilial forms, cannot be excluded. Linkage and whole exome sequencing studies have identified several susceptibility loci for familial ET, which only should explain a small percentage of ET heritability. Genome‐Wide Association Studies (GWAS) identified two genes related with ET risk, but the results of further meta‐analysis showed a modest increase in the risk for familial ET by two LINGO1 gene variants. Recently, missense mutations in TENM4 gene, a regulator of axon guidance and central myelination, possibly cause essential tremor. Several case–control association studies have shown association between the variants of certain genes in the risk for ET, but they deserve confirmation by further studies.

Key Concepts

  • Genetic factors play an important role in the risk for ET, as is supported by the high frequency of positive family history of tremor, and data from twin studies.
  • As not all cases of ET are explained by genetic factors, a possible role of unknown environmental factors has been suggested in sporadic ET.
  • The usual inheritance pattern is autosomal dominant with incomplete penetrance, although typical autosomal dominant, multifactorial, non‐Mendelian or other inheritance patterns have been described.
  • Linkage studies identified three susceptibility loci (ETM1, ETM2 and ETM3) for ET in several families, but they have not been replicated in others.
  • Whole exome sequencing studies have identified other three susceptibility loci (FUS/TLS or ETM4, HTRA2 and TENM4) in several families. These data await confirmation.
  • Genome‐Wide Association Studies (GWAS) described increased risk related with variants of LINGO1 (a meta‐analysis of studies showed a modest increase of risk in familial essential tremor) and SLC1A2 (not confirmed in a meta‐analysis) genes.
  • A recent study, which deserve further replication, has shown association between two variants of heme‐oxygenase 1 and 2 (HMOX1 and HMOX2), involved in iron metabolism, and the risk for ET.
  • Interaction between genes could possibly influence the risk for ET, as suggested in recent experimental models.

Keywords: essential tremor; family history; genetics; genetic polymorphisms; linkage studies, exome sequencing studies


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Further Reading

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Jiménez‐Jiménez, Félix Javier, Alonso‐Navarro, Hortensia, García‐Martín, Elena, Ortega‐Cubero, Sara, Pastor, Pau, and Agúndez, José AG(Jan 2016) Genetics of Essential Tremor. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025047]