Genetics of Parkinson disease

Abstract

An understanding of the genetic etiology of Parkinson disease (PD) has become imperative for the modern-day neurologist. Although genetic forms cause only a minority of PD, the disease mechanisms they elucidate advance the understanding of idiopathic cases. Moreover, recently identified susceptibility variants contribute to complex-etiology PD and broaden the contribution of genetics beyond familial and early-onset cases. Dominantly inherited monogenic forms mimic idiopathic PD and are caused by mutations or copy number variations of SNCA, LRRK2, and VPS35. On the other hand, early-onset forms are associated with PARKIN, PINK1, and DJ1 mutations, nominating mitochondrial dysfunction and oxidative stress as another important molecular pathway in the causation of the disease, in addition to alpha-synuclein accumulation. Common variants in GBA are consistently identified by association studies and may be considered to be a major risk gene for PD, with markedly reduced penetrance. Other genes have been proposed to be associated with PD; however, these only cause very rare forms, if at all. Current guidelines recommend testing for LRRK2 variants in familial PD or in specific populations (ancestry), and for the recessive genes in early-onset PD. However, gene panels have made testing for multiple forms of genetic PD a viable approach.

Keywords: DJ1; GBA; LRRK2; PARKIN; PINK1; Parkinson disease; SNCA; VPS35; genetic testing; genetics.