How often LRRK2 G2019S carriers get Parkinson's

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

The International LRRK2 Consortium: Daniel Healy, Mario Falchi, Sean O'Sullivan, Vincenzo Bonifati, Nicholas Wood, Andrew Lees and many others across 21 centres. Funding listed in the paper includes the UK Medical Research Council, Parkinson's UK (then the Parkinson's Disease Society), the US NIH (NINDS and the National Institute on Aging), the Michael J. Fox Foundation, the Volkswagen Foundation, the Safra Global Genetics Consortium and the US Department of Veterans Affairs.

What happened

The study (Lancet Neurology 7:583–590, July 2008) pooled data on LRRK2 mutations after the gene's discovery (landmark 7). It judged six mutations proven pathogenic. For the commonest, G2019S, frequency was about 1% of sporadic and 4% of hereditary Parkinson's, highest in the Middle East. Penetrance (the share of carriers who develop disease) was estimated in 1,045 people with LRRK2 mutations from 133 families: 28% by age 59, 51% by 69 and 74% by 79. The study was case-control: motor and non-motor symptoms (59 in all) in 356 LRRK2 patients were compared with 543 pathologically confirmed idiopathic cases, and LRRK2 disease was more benign.

Why it moved us toward a cure

The figures made LRRK2 carriers a defined group for genetic testing and, later, trials of LRRK2 inhibitors. Incomplete penetrance shows that a hidden factor, genetic or environmental, decides who falls ill, and finding it could point to protective strategies. A 2015 Ashkenazi Jewish study of 2,270 relatives of 474 patients found only 26% penetrance by age 80 (95% CI 18–36%), lower than the 2008 estimate, so the true figure depends on the population and how families were found (Neurology 85:89–95). A Chinese community study of G2385R, a different variant, found much lower penetrance, 10.3% by age 80 (Wang 2022, Eur J Neurol).

Outcome

Advanced: the estimates are used, but revised. The LRRK2 inhibitor BIIB122 failed in broad early Parkinson's in 2026 and continues in carriers (landmark 7). What the modifiers are is unresolved; a 2026 analysis of the PPMI cohort links changes in RNA processing (alternative polyadenylation) to which carriers develop symptoms, but it is one early finding (Yang 2026, Mov Disord). No correction or retraction was found for the Healy paper (Crossref, Europe PMC).

Sources

• Healy et al., Lancet Neurol 2008;7:583–590, DOI 10.1016/S1474-4422(08)70117-0 (Erasmus MC repository)
• Marder et al., Neurology 2015;85:89–95, DOI 10.1212/WNL.0000000000001708
• Wang et al., Eur J Neurol 2022;29:2639–2644, DOI 10.1111/ene.15417 · Yang et al., Mov Disord 2026;41:638–650, DOI 10.1002/mds.70119
• Not yet verified: the 2008 study's reason for higher figures (family-based ascertainment is the usual explanation, not confirmed here); other penetrance estimates beyond those above; confirmed modifiers of penetrance.