[paper] Protein-Truncating Variants in UQCRC1 Are Associated with Parkinson’s Disease
Our paper on rare genetic variants and Parkinson’s disease (PD) is published in npj Parkinson’s Disease! We used exome sequencing data from about half a million UK Biobank participants.
Why rare variants?
Genome-wide association studies (GWAS) are good at finding common variants, but each of those usually has only a small effect on disease risk. Rare variants, carried by fewer than 1 in 1,000 people, can have much larger effects. This is especially true for variants that break the protein entirely, such as protein-truncating variants (PTVs). Because they point directly at a gene’s function, rare variants are valuable for understanding disease biology and for finding drug targets.
The challenge is statistical. A single rare variant appears in so few people that testing it on its own has almost no power. Rare variant analysis therefore uses gene-based burden tests, which pool all qualifying rare variants in a gene and ask whether carriers have higher disease risk overall. Even then, very large sequenced cohorts are needed to find enough carriers. This is part of why small family-based or case-control studies often give conflicting results.
What we found
UQCRC1 encodes a subunit of mitochondrial complex III. Earlier studies linked it to PD in Taiwanese families, but most later studies failed to replicate the link. Using UK Biobank exome data (434,328 European-ancestry participants, 3,856 PD cases), we found:
- Rare high-confidence PTVs in UQCRC1 were associated with PD (OR = 6.59, P = 1.20 × 10⁻⁶). The result held after excluding carriers of known PD variants and close relatives.
- Rare missense variants showed no significant association.
- The PTVs are extremely rare: only 120 carriers among nearly half a million people. This helps explain why smaller studies gave inconsistent results, and it shows how important large population cohorts are for rare risk factors.