Although the majority of Parkinson’s disease cases are idiopathic, genetic factors are increasingly recognized as contributing to the disease. Approximately 10–15% of PD cases report a family history, and around 5% follow a Mendelian pattern of inheritance. Genetic mutations linked to PD are assigned the "PARK" designation, and to date, 23 PARK genes have been identified. Mutations in these genes may be inherited in an autosomal dominant or autosomal recessive manner, and their involvement in PD pathogenesis varies in terms of disease onset, clinical features, and progression.
The most well-known autosomal dominant mutations include those in the SNCA gene, which encodes α-synuclein, a protein that aggregates to form Lewy bodies—a pathological hallmark of PD. The LRRK2 gene, which encodes leucine-rich repeat kinase 2, is another significant gene implicated in autosomal dominant PD. Mutations in LRRK2, particularly the p.G2019S variant, are the most common cause of familial PD worldwide and also account for a small percentage of sporadic cases.
Autosomal recessive forms of PD are typically associated with earlier onset and slower disease progression. Genes involved in mitochondrial function, such as PRKN (parkin), PINK1, and DJ-1, are commonly implicated in autosomal recessive PD. These genes play a crucial role in mitochondrial quality control, with mutations leading to impaired mitophagy and increased susceptibility to oxidative stress, which contributes to dopaminergic neuron degeneration. Mutations in PRKN are the most common cause of early-onset autosomal recessive PD, accounting for up to 50% of cases in some populations.
In addition to monogenic forms of PD, several genetic risk factors have been identified that increase susceptibility to idiopathic PD. One of the most significant is the GBA1 gene, which encodes the lysosomal enzyme β-glucocerebrosidase. Mutations in GBA1 are associated with both Gaucher disease and an increased risk of PD. Other genetic risk factors include variants in the MAPT gene, which encodes the protein tau, and the HLA-DQB1 gene, part of the major histocompatibility complex. These genetic discoveries have expanded our understanding of the molecular mechanisms underlying PD and may eventually lead to targeted therapies for different genetic subtypes of the disease.
