90 genetic risk signals

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

Mike Nalls, Cornelis Blauwendraat, Andrew Singleton and colleagues from the International Parkinson's Disease Genomics Consortium, 23andMe, UK Biobank and others.

What happened

A meta-analysis of 17 datasets of European-ancestry people (7.8 million variants; 37,688 cases, 18,618 UK Biobank "proxy" cases, meaning people with a first-degree relative with Parkinson's; and 1.4 million controls) found 90 independent signals across 78 genomic regions, 38 of them new (in 37 loci). Together the variants explained 16–36% of the heritable risk, depending on the assumed disease prevalence. Mendelian randomisation linked likely causal genes to 70 signals, and expression was most enriched in brain neurons. Lancet Neurol 2019;18:1091–1102 (PMID 31701892; one commentary, no correction found). The 23andMe data came from its earlier Parkinson's web study (Chang 2017) plus newer participants; 23andMe's own summary statistics are available only under an agreement with the company.

• Prizes. The 2024 Breakthrough Prize in Life Sciences (announced September 2023) went to Andrew Singleton, Thomas Gasser and Ellen Sidransky for identifying GBA1 and LRRK2 as Parkinson's genes; it was not awarded for this GWAS (Breakthrough Prize).

Why it moved us toward a cure

It gave an unbiased map of disease biology and a supply of genetically supported drug targets. Storm et al. 2021 applied Mendelian randomisation to over 3,000 druggable genes and proposed 23 candidate mechanisms.

It extends the first genome-wide scans and the 2014 meta-analysis (landmark 237).

Outcome

Advanced, and since extended: a multi-ancestry study (Kim et al., Nature Genetics 2024;56:27–36, DOI 10.1038/s41588-023-01584-8) used 49,049 cases, 18,785 proxy cases and 2,458,063 controls of European, East Asian, Latin American and African ancestry, found 78 loci including 12 potentially new ones, and fine-mapped 6 putative causal variants. A GP2 preprint (medRxiv, March 2025; not peer reviewed) reports 134 loci (59 new) and 157 independent signals in 63,555 cases, 17,700 proxy cases and 1.75 million European-ancestry controls.

Sources

• Nalls et al., Lancet Neurol 2019, DOI 10.1016/S1474-4422(19)30320-5
• Kim et al., Nat Genet 2024, DOI 10.1038/s41588-023-01584-8
• GP2 Consortium preprint, medRxiv 2025, DOI 10.1101/2025.03.14.24319455
• Breakthrough Prize 2024 laureates
• Storm et al., Nat Commun 2021;12:7342, DOI 10.1038/s41467-021-26280-1
• Not yet verified: whether the 2025 GP2 meta-analysis has been peer reviewed and published.