Lysosomal storage disease genes as a group raise risk

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

Laurie Robak, Joshua Shulman (Baylor College of Medicine and Texas Children's Hospital) and colleagues, with Iris Jansen, Peter Heutink and the International Parkinson's Disease Genomics Consortium (Brain, 2017).

What happened

The commonest genetic risk factor, GBA (landmark 16), is a gene that causes Gaucher disease when both copies are faulty. Gaucher is a lysosomal storage disease, one of a group of inherited diseases in which the cell's recycling compartment, the lysosome, cannot break down some material. Robak et al. asked whether other such genes also matter.

• Discovery cohort. Whole-exome sequencing (reading all protein-coding DNA) in 1,156 people with Parkinson's and 1,679 controls. A gene-set test covering 54 lysosomal storage disease genes found a significant excess of rare, likely damaging variants in patients.
• Without GBA. The signal remained after GBA was removed.
• Replication. It held in two further cohorts: 436 cases and 169 controls with exome sequencing, and 6,713 cases and 5,964 controls with genotyping.
• Genes. Associations at GBA and SMPD1 were confirmed. CTSD, SLC17A5 and ASAH1 were named as new candidates.
• Burden. In the discovery set, 56% of patients had at least one putative damaging variant in one of these genes, and 21% had more than one.

The authors suggested several small genetic hits may add up to weaken lysosome function.

Why it moved us toward a cure

It broadened the idea of GBA from a single gene to a pathway. In my reading, that supports trying to boost the lysosome in many patients, not only GBA carriers (landmark 35), and it fits the lysosomal signals later seen in genome-wide studies (landmark 19). It is also a reason the two GBA drug trials in carriers (landmark 69, landmark 235) each tested one part of a wider system.

Outcome

Advanced. The result was replicated within the paper. A Chinese mainland cohort (Zhao et al., 2021; 3,879 patients, 2,931 controls, 69 lysosomal storage disease genes) found a significant burden that held after excluding GBA in familial or early-onset patients but not in sporadic late-onset ones, with SMPD1 only suggestive. A 2026 study of 8,267 patients and 68,208 controls (Senkevich et al., Mov Disord) tested 36 lysosomal genes and named different top genes (ST3GAL3, and NAGLU and ST3GAL5 in early-onset), so the individual genes beyond GBA are not settled. No correction or retraction was found; two 2018 Brain letters on the same gene set in multiple system atrophy are not criticisms of this paper.

Sources

• Robak et al., Brain 2017;140(12):3191–3203, DOI 10.1093/brain/awx285, PMID 29140481 (abstract and author list via Europe PMC)
• Zhao et al., Front Aging Neurosci 2021, DOI 10.3389/fnagi.2021.749109 · Senkevich et al., Mov Disord 2026, DOI 10.1002/mds.70391 (abstracts via Europe PMC)
• Not yet verified: funders of the Robak study; which cohorts were used for replication beyond the sizes above; which disease SMPD1 causes (not read in a source here).