Advances in understanding genomic markers and pharmacogenetics of Parkinson’s disease

ABSTRACT

Introduction: The inheritance pattern of Parkinson’s disease (PD) is likely multifactorial (owing to the interplay of genetic predisposition and environmental factors). Many pharmacogenetic studies have tried to establish a possible role of candidate genes in PD risk. Several studies have focused on the influence of genes in the response to antiparkinsonian drugs and in the risk of developing side-effects of these drugs.

Areas covered: This review presents an overview of current knowledge, with particular emphasis on the most recent advances, both in case-control association studies on the role of candidate genes in the risk for PD as well as pharmacogenetic studies on the role of genes in the development of side effects of antiparkinsonian drugs. The most reliable results should be derived from meta-analyses of case-control association studies on candidate genes involving large series of PD patients and controls, and from genome-wide association studies (GWAS).

Expert opinion: Prospective studies of large samples involving several genes with a detailed history of exposure to environmental factors in the same cohort of subjects, should be useful to clarify the role of genes in the risk for PD. The results of studies on the role of genes in the development of side-effects of antiparkinsonian drugs should, at this stage, only be considered preliminary.

KEYWORDS:

• Parkinson’s disease
• pharmacogenetics
• polymorphisms
• risk factors
• side effects

Article highlights.

• Several gene polymorphisms seem to be associated with the risk for PD according to recent studies (most of them meta-analyses).

• Gene polymorphisms possibly associated with PD risk include those of genes involved in detoxification mechanisms (CYP2D6, GSTM1, GSTT1), dopamine metabolism (DRD3, SLC6A3, MAOA, MAOB, MTHFR), oxidative stress (HFE, NFE2L2) inflammatory processes (TNF, A2M, TREM2), and other putative relations (MAPT, STH, ESR1, ESR2, VDR, SEMA5A, GRN, and GSK3β.

• MAPT gene polymorphisms are strongly associated with the risk for PD according to data from meta-analyses of case-control association studies and from GWAS.

• SNCA and LRRK2 genes have shown an association with the risk for PD in GWAS, while meta-analyses of case-control association studies have suggested an association with certain polymorphisms in the PARK2, PARK16, PARK5, GIGYF2, and GBA genes.

• GBA gene mutations seem to be associated with the risk for dementia in PD; several variants in the DRD3, DRD2, and SLC6A3 genes with the response to antiparkinsonian drugs; variants in the ANKK1, DRD3, and LRRK2 genes, and mutations in the GBA gene with the risk for levodopa-induced-dyskinesias; several variants in the COMT and LRRK2 genes with the risk for motor fluctuations; and variants in the DRD1 and GRIN2B genes with the risk of developing ICD.

This box summarizes key points contained in the article.

Acknowledgments

Professor James McCue revised in detail the quality of the English language.

Declaration of Interest

This work was supported in part by Grants PI12/00241, PI12/00324 and RETICS RD12/0013/0002 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, and GR15026 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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