| Summary: | This thesis reports on the first genome wide association study (GWAS) for genetic variants conferring risk for essential tremor (ET). It shows that the single nucleotide polymorphism (SNP) rs9652490 in intron 3 of LINGO1, a gene important in regulating axon regeneration and oligodendrocyte maturation, is associated with essential tremor (ET). It furthermore explores the effect of the variant on a range of clinical characteristics related to essential tremor. A marker in LINGO1 was identified through a GWAS approach, showing genome wide significant association with essential tremor, with an odds ratio (OR) of 1.55 and P-value (P) of 1.2x10^(-9). When the discovery dataset was excluded and the analysis done on only the follow-up material, the odds ratio was 1.44, with a P-value of 0.001. To further clarify the role of LINGO1 in the aetiology of ET, this study also looked at the effect of the SNP rs9652490 on a range of ET characteristics: sex, age at onset, presence or absence of family history and head tremor, response to propranolol medication and alcohol, and the outcome of finger-nose and spirography tests (Archimedes spirals). ET subjects with information on clinical characteristics from four countries, Iceland (N = 230), Germany (N = 225), USA (N = 111) and Austria (N = 81) were genotyped for marker rs9652490. Controls from the same populations were also genotyped for marker rs9652490 (N = 32,811; 333; 387; and 241, respectively). The ET individuals were divided into four groups depending on the age at onset: early onset (0-19 years old, N = 220), intermediate onset (20-39 years old, N = 158), late onset (40-59 years old, N = 158) and very late onset (60 years or older, N = 107). All four groups showed significant association of rs9652490 to ET, and the odds ratio was not significantly different in the four age groups. Thus, rs9652490 confers risk of ET for all ages of onset. There was significant association of allele G of rs9652490 to ET irrespective of presence or absence of family history (ORs 1.74 and ...
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