Summary
A study of 62,560 individuals across diverse ancestries found no evidence that rare variants in TMEM106B are associated with Parkinson's disease risk. The findings suggest the gene's rare variation does not play a major role in PD susceptibility, despite evidence that TMEM106B expression is altered in the brains of people with the disease.
Contents
- A null result for rare TMEM106B variation
- Study design and data sources
- What this means for Parkinson's research
- Limitations
A null result for rare TMEM106B variation
Recent evidence has shown that TMEM106B expression is reduced in the brains of people with Parkinson's disease. This raised the possibility that genetic variation in the gene might contribute to disease risk. A new study examining rare variants across more than 62,000 individuals found no such association.
The researchers analysed whole-genome sequencing data from 22,010 Parkinson's disease cases and 40,550 controls drawn from the Global Parkinson's Genetics Program, the Accelerating Medicines Partnership in Parkinson's Disease, and the UK Biobank. The cohorts spanned diverse ancestries. They identified 4,581 unique rare variants in TMEM106B.
No pathogenic or likely pathogenic variants classified by ClinVar were observed in any cohort. Statistical analysis found no evidence that rare coding variants in TMEM106B were associated with Parkinson's disease risk, whether assessed individually or as a cumulative burden.
The findings suggest that rare variation in TMEM106B does not play a major role in Parkinson's disease susceptibility across the populations studied.
Study design and data sources
The analysis relied on whole-genome sequencing data from three large datasets. GP2 contributed data from diverse populations globally. AMP-PD provided additional sequencing data, and the UK Biobank supplied a large European-ancestry cohort. The study was completed under UK Biobank application 45551.
The authors used a variant-level analysis and a gene-burden test to assess whether rare coding variants showed any association with disease status. All code and analysis pipelines were made publicly available on GitHub with a persistent Zenodo identifier.
What this means for Parkinson's research
The result is a null finding, but it carries weight because of the size and diversity of the cohort. Prior evidence linking TMEM106B to Parkinson's came primarily from expression studies in brain tissue, which cannot by themselves establish whether genetic variants drive disease risk. A large sequencing effort was needed to test that question directly.
The absence of an association at the rare-variant level does not mean TMEM106B has no role in Parkinson's biology. Common variants, regulatory elements outside the coding sequence, or gene-expression changes secondary to the disease process could still be relevant. The study examined only rare coding variants; it cannot speak to the broader functional landscape of the gene.
Limitations
The work is a preprint posted to medRxiv on 2 October 2026 and has not yet undergone peer review. It is an observational genetic association study, which can identify statistical associations but cannot establish causation. The analysis focused on rare coding variants; common variants and non-coding regulatory variation were not assessed. The cohorts, while large and diverse, may not capture all population groups.