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

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• 作者：Owen A  ; Ross DrPhD^a ;   ; ^{ross.owen@mayo.edu} ; Alexandra I  ; Soto-Ortolaza BSc^a ; Michael G  ; Heckman MS^b ; Jan O  ; Aasly ProfMD^d ; Nadine  ; Abahuni MD^e ; Grazia  ; Annesi ProfPhD^f ; Justin A  ; Bacon BSc^a ; Soraya  ; Bardien PhD^g ; Maria  ; Bozi MDⁱ ; Alexis  ; Brice ProfMD^j ;   ; ^k ;   ; ^l ;   ; ^m ; Laura  ; Brighina MDⁿ ; Christine  ; Van Broeckhoven ProfPhD^o ;   ; ^p ; Jonathan  ; Carr ProfMD^h ; Marie-Christine  ; Chartier-Harlin ProfMD^q ;   ; ^r ; Efthimios  ; Dardiotis MD^s ;   ; ^t ; Dennis W  ; Dickson ProfMD^a ; Nancy N  ; Diehl BS^b ; Alexis  ; Elbaz ProfMD^u ;   ; ^v ; Carlo  ; Ferrarese ProfMDⁿ ; Alessandro  ; Ferraris MD^w ; Brian  ; Fiske PhD^x ; J Mark  ; Gibson ProfMD^y ;   ; ^&Dagger ; ; Rachel  ; Gibson PhD^z ; Georgios M  ; Hadjigeorgiou MD^s ;   ; ^t ; Nobutaka  ; Hattori ProfMD^aa ; John PA  ; Ioannidis ProfMD^ab ;   ; ^ac ; Barbara  ; Jasinska-Myga MD^ad ; Beom S  ; Jeon ProfMD^ae ; Yun Joong  ; Kim ProfMD^ag ; Christine  ; Klein ProfMD^ah ; Rejko  ; Kruger MD^ai ; Elli  ; Kyratzi MD^aj ; Suzanne  ; Lesage PhD^j ;   ; ^k ;   ; ^l ; Chin-Hsien  ; Lin MD^ak ; Timothy  ; Lynch ProfFRCPI^al ; Demetrius M  ; Maraganore ProfMD^am ; George D  ; Mellick PhD^an ; Eugé ; nie  ; Mutez MD^q ;   ; ^r ;   ; ^ao ; Christer  ; Nilsson ProfPhD^ap ; Grzegorz  ; Opala ProfMD^ad ; Sung Sup  ; Park ProfMD^af ; Andreas  ; Puschmann MD^ap ;   ; ^aq ; Aldo  ; Quattrone ProfMD^ar ; Manu  ; Sharma PhD^ai ; Peter A  ; Silburn ProfPhD^as ; Young Ho  ; Sohn ProfMD^at ; Leonidas  ; Stefanis MD^aj ; Vera  ; Tadic MD^ah ; Jessie  ; Theuns PhD^o ;   ; ^p ; Hiroyuki  ; Tomiyama MD^aa ; Ryan J  ; Uitti ProfMD^c ; Enza Maria  ; Valente ProfMD^w ; Simone  ; van de Loo PhD^e ; Demetrios K  ; Vassilatis PhD^aj ; Carles  ; Vilariñ ; o-Gü ; ell PhD^au ; Linda R  ; White ProfPhD^av ; Karin  ; Wirdefeldt MD^aw ; Zbigniew K  ; Wszolek ProfMD^c ; Ruey-Meei  ; Wu ProfMD^ax ; Matthew J  ; Farrer ProfPhD^a ;   ; ^au ; on behalf of the Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium
• 刊名：Lancet Neurology
• 出版年：2011
• 出版时间：October 2011
• 年：2011
• 卷：10
• 期：10
• 页码：898-908
• 全文大小：271 K

文摘

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¨CBerber) 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?40 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab¨CBerber 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?¡¤78; p=0¡¤0012) and Asian individuals (A419V, 2¡¤27, 1¡¤35?¡¤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¨CBerber series (combined odds ratio 0¡¤82, 0¡¤72?¡¤94; p=0¡¤0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1¡¤73, 1¡¤20?¡¤49; p=0¡¤0026), but no association was noted for R1628P (0¡¤62, 0¡¤36?¡¤07; p=0¡¤087). In the Arab¨CBerber series, Y2189C showed potential evidence of risk association with PD (4¡¤48, 1¡¤33?5¡¤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.

Funding

Michael J Fox Foundation and National Institutes of Health.