Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case—control study

Dr Owen A Ross PhD a

, Alexandra I Soto-Ortolaza BSc a, Michael G Heckman MS b, Prof Jan O Aasly MD d, Nadine Abahuni MD e, Prof Grazia Annesi PhD f, Justin A Bacon BSc a, Soraya Bardien PhD g, Maria Bozi MD i, Prof Alexis Brice MD j k l m, Laura Brighina MD n, Prof Christine Van Broeckhoven PhD o p, Prof Jonathan Carr MD h, Prof Marie-Christine Chartier-Harlin MD q r, Efthimios Dardiotis MD s t, Prof Dennis W Dickson MD a, Nancy N Diehl BS b, Prof Alexis Elbaz MD u v, Prof Carlo Ferrarese MD n, Alessandro Ferraris MD w, Brian Fiske PhD x, Prof J Mark Gibson MD y ‡, Rachel Gibson PhD z, Georgios M Hadjigeorgiou MD s t, Prof Nobutaka Hattori MD aa, Prof John PA Ioannidis MD ab ac, Barbara Jasinska-Myga MD ad, Prof Beom S Jeon MD ae, Prof Yun Joong Kim MD ag, Prof Christine Klein MD ah, Rejko Kruger MD ai, Elli Kyratzi MD aj, Suzanne Lesage PhD j k l, Chin-Hsien Lin MD ak, Prof Timothy Lynch FRCPI al, Prof Demetrius M Maraganore MD am, George D Mellick PhD an, Eugénie Mutez MD q r ao, Prof Christer Nilsson PhD ap, Prof Grzegorz Opala MD ad, Prof Sung Sup Park MD af, Andreas Puschmann MD ap aq, Prof Aldo Quattrone MD ar, Manu Sharma PhD ai, Prof Peter A Silburn PhD as, Prof Young Ho Sohn MD at, Leonidas Stefanis MD aj, Vera Tadic MD ah, Jessie Theuns PhD o p, Hiroyuki Tomiyama MD aa, Prof Ryan J Uitti MD c, Prof Enza Maria Valente MD w, Simone van de Loo PhD e, Demetrios K Vassilatis PhD aj, Carles Vilariño-Güell PhD au, Prof Linda R White PhD av, Karin Wirdefeldt MD aw, Prof Zbigniew K Wszolek MD c, Prof Ruey-Meei Wu MD ax, Prof Matthew J Farrer PhD a au, on behalf of the Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium

Summary

Background

Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.

Methods

LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab—Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.

Findings

121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab—Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15—1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35—3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab—Berber series (combined odds ratio 0·82, 0·72—0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20—2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36—1·07; p=0·087). In the Arab—Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33—15·09; p=0·012).

Interpretation

The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.