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25-09-2011 | Genetics | Article

LRRK2 variants more important than thought in PD risk

Abstract

Free abstract

MedWire News: A large genetic study has identified several new variants of the leucine-rich repeat kinase 2 gene (LRRK2) that affect risk for Parkinson's disease (PD), including a haplotype that is protective across three ethnic groups.

"The identification of common variants that affect risk clearly shows a greater role for LRRK2 in idiopathic disease than previously thought," the researchers write in The Lancet Neurology.

Previous genome-wide association studies (GWAS) identified a role for LRRK2 mutations in PD, with one variant (G2019S) present in up to 30% of Arab-Berber patients with PD.

For the current case-control study, Owen Ross (Mayo Clinic, Jacksonville, Florida, USA) and colleagues focused specifically on the role of LRRK2 in PD across three ethnic groups. They genotyped 15,540 individuals, comprising 6995 White PD patients and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls for 121 LRRK2 variants.

Of the LRRK2 variants genotyped, just 26 of these occurred in more than 0.5% of any ethnic group, and only 13 occurred in more than 0.5% of all three groups.

The protective haplotype consisted of the minor alleles of the LRRK2 variants N551K, R1398H, and K1423K (G, A, and A, respectively). It was present in more than 5% of all three groups, and was associated with an overall 18% reduction in the odds for PD.

The team also identified a new risk variant for PD in White people - M1646T, the C allele of which increased the odds for PD 1.43-fold - and one in Asian people - A419V, the T allele of which raised the odds for PD 2.27-fold.

This brings the reported number of LRRK2 risk variants in Asians to three, say the researchers. Of the other two, the G allele of G2385R raised the odds for PD 2.49-fold in the current study, but R1628P was not associated with PD risk.

Ross et al also identified a new variant - Y2189C - that appeared to raised the odds for PD in Arab-Berber people, although the 4.48-fold risk increase associated with the G allele was less strongly significant than those seen for the other identified risk variants.

In an accompanying commentary, Eng-King Tan (Duke-National University of Singapore) said that the findings "will be a vital resource for other researchers."

But he added: "To many clinicians, knowing that at-risk healthy carriers of low-penetrance gene variants have a 1-10% lifetime risk of PD has little clinical relevance unless a therapeutic intervention is available."

Tan noted that the identified mutations might prove to be viable drug targets, as has been shown in animal studies.

"Research strategies that integrate GWAS and more detailed sequencing with epigenomic expression, biological pathways, proteomics, and functional imaging data might lead to new potential interventions, and carriers of particular gene variants could be candidates for clinical trials of targeted neuroprotective drugs," he concluded.

By Eleanor McDermid

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