The tyrosine hydroxylase (TH) gene encodes a monoxygenase that catalyzes the rate limiting step in dopamine
biosynthesis. A hallmark of Parkinson’s disease (PD) is the loss of dopaminergic neurons in the substantia nigra.
Consistent with the essential role of TH in dopamine homeostasis, missense mutations in both alleles of TH have been
associated with severe Parkinsonism-related phenotypes including infantile Parkinsonism. It has been speculated for a
long time that genetic variants in the TH gene modify adult-onset PD susceptibility but the answer has not been clear.
Genetic variants (both sequence variations and structural variations) can be classified into three categories based on their
relative frequency in population: common variants (polymorphisms), rare variants and mutations. Each of these factors
has a different mode in influencing the genetic risk and often requires different approaches to decipher their contributions
to the disease. In the past few years, the revolutionary advances in genomic technology have allowed systematic
evaluations of these genetic variants in PD, such as the genome-wide association study (GWAS, to survey common
variants), copy number variation analysis (to detect structural variations), and massive parallel next generation sequencing
(to detect rare variants and mutations). In this review, we have summarized the latest evidence on TH genetic variants in
PD, including our ongoing effort of using whole exome sequencing to search for rare variants in PD patients.
Keywords: Rare variant, copy number variations, Parkinson’s disease, genetic association, tyrosine hydroxylase.
polymorphism, next generation sequencing, genome wide association study.
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