Meta-analysis of GWAS identifies 17 new Parkinson disease (PD) risk loci: key role for autophagy and lysosomal biology ??!!??

Parkinson disease (PD) is the second most common neurodegenerative disorder (Alzheimer disease being first). The prevalence of PD is 3–4% in individuals over 80 years of age. PD is characterized by loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies. These neuropathologies in affected individuals lead primarily to motor-related symptoms (e.g. finger dexterity, walking). Early-onset, familial PD (beginning at age 60 years or earlier) accounts for a small fraction of cases, but the identified associated genes, including LRRK2, GBA, and SNCA, provide insight into disease pathogenesis. For the later-onset, common form of PD, at least 24 loci have been associated at a genome-wide significant level with disease risk in individuals of European ancestry. The narrow-sense heritability (h2) explained by the confirmed PD risk loci is low (0.033); for those who do not know, h2 denotes “heritability index” –– where a trait that is 100% inherited is 1.0 and 100% environmental is 0.0%.

However, the heritability [i,e. the proportion of known variation among individuals in a given population due to genetic variation] explained by the 24 common variant loci is estimated at less than 23%, which suggests that additional loci with smaller effect-sizes remain to be discovered. Therefore, to search for additional loci, authors [see attached report] carried out a GWAS, comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of more than 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. Authors then tested 35 loci (P <1 × 10–6) in a replication cohort of 5,851 cases and 5,866 controls [replication cohorts are mandated in order to publish in Nature Genetics and certain other high-end journals]. Authors identified 17 novel risk loci (P <5.0 x 10–8) in the combined analysis of 26,035 cases and 403,190 controls. Authors used a neurocentric strategy to assign candidate risk genes to the loci. In 29 of the 41 PD loci (i.e. 24 + 17 new variants), they identified protein-altering or cis–expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant. Their exciting findings strongly suggested a key role for autophagy and lysosomal biology [normal physiological processes that are involved in destruction of cells in the body; autophagy maintains normal functioning by protein degradation, as well as turnover of destroyed cell organelles for new cell formation –– seen especially during cellular stress] in PD risk, which suggests potential new drug targets for PD..! Nature Genetics Oct 2o17; 49: 1511–1516

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.