Linking LINGO1 to Essential Tremor

of ET is problematic without a biological or NEWS AND COMMENTARY objective diagnostic marker. ET is essentially a clinical diagnosis and despite proposed diagnostic criteria by experts in the field, we do LINGO1 and Essential Tremor: linking the shakes not know for certain whether ET is a single ...... disorder or a disease syndrome with varied etiologies.1 Some people with ET also have Linking LINGO1 to essential tremor other associated movement disorders, while others progress to develop Parkinson’s disease Eng-King Tan years after the initial ET diagnosis. Even ...... limited post-mortem studies seem to suggest that the condition is likely to be hetero- European Journal of Human Genetics (2010) 18, 739–740; doi:10.1038/ejhg.2010.25; geneous. Most cases have cerebellar changes published online 7 April 2010 without Lewy bodies, whereas intriguingly some cases have brainstem Lewy bodies.7 It is arguable whether the inclusion of the latter ssential tremor (ET), one of the most of ‘definite’, ‘probable’ or ‘possible’ cases and group would compound genetic association E common neurological conditions, is showed that the strength of association with studies. One study showed that one in three characterized by postural and action tremor.1 rs9652490 was stronger in those with a more patients with tremor have been wrongly diag- The prevalence has been reported to be as definitive diagnosis. They also alluded to the nosed as having ET.8 These problems are high as 39 cases per 1000. As a family history interesting observation that three other SNPs further exacerbated by the varying diagnostic of ET is frequently present among those within a 2.3k haplotype (rs177008, rs13313467 criteria used by authors with varying degrees affected, extensive efforts have been taken and rs8028808) were associated with younger of expertise in managing this disorder. to identify the responsible genes. However, ET (age at onset o40 years) patients. The Although most studies would suggest that at though linkage regions in chromosome 3q13 study by Clarke et al, together with the two least 40À50% of their cohorts have a positive (ETM1), 2p22-p25 (ETM2) and 6p23 have currently available replication studies,5,6 pro- family history, many genetic association been identified in Icelandic and North vides collaborative evidence that LINGO1 studies do not attempt to differentiate the American families, the causative gene has rs9652490 is associated with ET. However, familial from the sporadic group. For example, yet to be unraveled.2 The first genomewide the varying strength of association with addi- in the GWAS study,3 familial and sporadic ET association study (GWAS) in ET identified a tional SNPs and the implication of different waseitheranalyzedasagroupornoinforma- sequence variant (rs9652490 G allele) of the alleles of rs9652490 also suggest that this SNP tion on the specific group of ET patients was LINGO1 gene to be a risk factor in European may not be the functional variant but may be provided. It would be interesting to determine and American populations.3 This finding is in linkage disequilibrium with unknown func- how the overall effect size of the association exciting as the estimated population-attribu- tional variants in the vicinity. Furthermore, will be affected if only familial or sporadic table risk of the variant (20%) is relatively the SNP is located in intron 3 and there is no cases were examined. To compound the pro- high and the effect appears to be driven clear evidence that it is predicted to alter blem, many patients may not be aware of other primarily by a specific allele and not by the splicing or affect protein function. family members with ET and their condition surrounding SNPs. Some skepticism remains Based on current limited evidence, it is may remain undiagnosed. One study esti- as ET is widely recognized as a clinically reasonable to be optimistic that elucidation mated the sensitivity of family history data heterogeneous condition and clinical diagno- of the link between LINGO1 and ET is an given by ET patients to be around 40%.9 This sismaynotbealwaysaccurate. important first step in genetic dissection of poses a challenge in clinical classification and Replication in independent cohorts and the condition. However, the current excite- canhaveanimpactontheinterpretation ethnicity remains the barometer for the vali- ment has to be somewhat tempered with of large-scale population genetic studies in dity of genetic association studies. Clark et al4 a reminder that initial observations linking which family history may well be relevant. conducted a replication study in a North HS1-BP3 and DRD3 gene variants to ET The issue of age-dependent penetrance American cohort and genotyped 15 SNPs in have not been consistently replicated. While in ET is rarely highlighted. Similar to ET the LINGO1 gene. Compared with most ET we draw lessons from previous experiences, it patients, many apparent healthy controls with genetic studies, this study helps to provide is timely to highlight the potential pitfalls in essential tremor may not be aware of additional insights primarily through a more dealing with genetics of complex disorders their tremor. Thus, in ET case–control robust methodology, whereby cases and such as ET, and the unique problems specific studies, the controls should preferably be controls were recruited as part of an ongoing to the condition, some of which have been physically examined by an expert or subjected epidemiological study, all of them were exemplified in the GWAS study3 and in the to standardized screening procedures, and clinically well annotated, and the diagnostic report by Clarke et al.4 their ages should preferably be similar or criteria were applied uniformly through stan- Advances in technological genotyping greater than those of ET patients. In the dardized screening and examination. Specifi- platforms have improved the sensitivity of GWAS study3 the 14 393 Icelandic controls cally, Clarke et al were able to evaluate subsets GWAS, and, with the lowering of financial were apparently not screened for ET, and cost, accessibility and feasibility, this will in the two follow-up studies in Austria and Dr E-K Tan is at the Department of Neurology, Singapore become less of an issue in most countries. Germany the median age of controls was General Hospital, National Neuroscience Institute, However, it is important to recognize that the about 20–25 years lesser than that of ET Duke-NUS Graduate Medical School, Outram Road, Singapore 169608, Singapore. Fax: +65 6220 3321; major limitation in genetic association studies patients. It is unclear how these would have E-mail: [email protected] in ET is a fundamental one. A case definition influenced the reported effect size difference. News and Commentary 740

It is also interesting to highlight that that LINGO1 is involved in the regulation of 1 Louis ED: Essential tremor. Lancet Neurol 2005; 4: 100–110. genetic studies on ET in the literature neuronal survival and axonal regeneration 2 Tan EK, Schapira AH: Hunting for genes in essential (including the GWAS study) involved a rela- warrant further efforts to evaluate this locus tremor. Eur J Neurol 2008; 5: 889–890. tively small number of ET cases. Thus, small across different races and a multi-center 3 Stefansson H, Steinberg S, Petursson H et al: Variant in the sequence of the LINGO1 gene confers risk of essen- effect size difference or rare at-risk variants collaborative effort to better define subsets tial tremor. Nat Genet 2009; 41: 277–279. may be missed. The current replication study of ET patients who are at greater risk and to 4 Clark N, Park N, Kisselev S et al: Replication of LINGO1 by Clark et al4 recruited 257 ET cases and the explore the potential gene–environmental gene association with essential tremor in a North American population. Eur J Hum Genet 2010; 18: sample size was underpowered for many of effects. Multiple approaches using different 838–843. the subset analyses. It is possible that there is genetic methodologies are likely to be 5 Vilarin˜ o-Guëll C, Ross OA, Wider C et al:LINGO1 rs9652490 is associated with essential tremor and a selection bias for the more severe cases that required to uncover additional variants or Parkinson disease. Parkinsonism Relat Disord 2010; present to the tertiary centers and the inves- causative genes and susceptibility loci. 16:109–111. tigators are only analyzing the ‘tip of the 6 Tan EK, Teo YY, Prakash KM et al:LINGO1variant increases risk of familial essential tremor. Neurology iceberg’. The vast majority of ET patients in CONFLICT OF INTEREST 2009; 73: 1161–1162. the community may well have a milder The author declares no conflict of interest. 7 Louis ED, Faust PL, Vonsattel JP et al: Neuropathologi- phenotype and are unlikely to participate in cal changes in essential tremor: 33 cases compared with 21 controls. Brain 2007; 130 (Pt 12): 3297–3307. studies; thus, specific endo-phenotypes may Acknowledgements 8 Jain S, Lo SE, Louis ED: Common misdiagnosis of a be missed. I am supported by grants from the National Medical common neurological disorder: how are we misdiagnosing essential tremor? Arch Neurol 2006; 63: 1100–1104. Despite these caveats, the positive replica- Research Council, Duke-NUS Graduate Medical 9 Prakash KM, Tan EK: Validity of family history in essential tion of rs9652490 and the biological evidence School and Singapore Millennium Foundation’ tremor. Parkinsonism Relat Disord 2008; 14: 151–153.

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