Parkinson's disease and low frequency alleles found together throughout LRRK2

Mutations within LRRK2, most notably p.G2019S, cause Parkinson's disease (PD) in rare monogenic families, and sporadic occurrences in diverse populations. We investigated variation throughout LRRK2 (84 SNPs; genotype or diplotype found for 49 LD blocks) for 275 cases (European ancestry, onset at age 60 or older) and 275 neurologically healthy control subjects (NINDS Neurogenetics Repository). Three grade-of-membership groups, i.e. genetic risk sets, were identified that exactly matched many subjects (cases: 46, 4, 137; controls: 0, 178, 0), and distinguished 94% of the subjects (i.e. >50% likeness to one set). Set I, affected, carried certain low frequency alleles located in multiple functional domains. Set II was unaffected. Set III, also affected, resembled set II except for slightly elevated frequencies of minor alleles not defining set I. We conclude that certain low frequency alleles distributed throughout LRRK2 are a genetic background to a third of cases, defining a distinct subset.