SNCA Rep1 promoter variant raises 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

Demetrius Maraganore (Mayo Clinic), Mariza de Andrade, Alexis Elbaz, Matthew Farrer, John Ioannidis, Rejko Krüger, Walter Rocca and colleagues from 18 sites in a global genetics consortium (JAMA 2006). The abstract lists US NIH (NINDS, NIEHS) grants among the support.

What happened

Rare families with extra copies of SNCA (landmark 14) showed that more synuclein is enough to cause disease. Many small studies had linked REP1, a dinucleotide repeat (a short DNA unit repeated a variable number of times) in the gene's promoter (its on-switch), to Parkinson's, but the results disagreed. The consortium pooled individual-level data. Of 18 sites, 11 passed strict checks on genotype quality. They supplied 2,692 cases and 2,652 controls, with no sign of differences between studies.

REP1 alleles differed between cases and controls (P<.001). Genotypes defined by the 263-base-pair allele carried an odds ratio of 1.43 (95% CI 1.22–1.69; P<.001 for trend) for disease. Haplotypes (sets of nearby variants inherited together) that included REP1 were also associated. REP1 did not change age at onset.

Why it moved us toward a cure

It gave a large, quality-checked sign that a common variant near SNCA raises risk, three years before genome-wide scans found the same locus (landmark 237). A promoter change is the kind of variant that could shift how much synuclein is made, though this paper did not test that. The later enhancer finding (landmark 49) took this further.

Outcome

Advanced. The association is accepted and was built on. A 2009 study in mice carrying the whole human SNCA gene found that the longer, risk-linked REP1 allele gave 1.7-fold more human SNCA mRNA and 1.25-fold more protein in brain than the shorter allele, in animals with two copies of each (Cronin 2009, Hum Mol Genet). That points to more synuclein as the mechanism, but it is mouse data, and this 2006 paper did not test it. No correction or retraction was found (Crossref, Europe PMC).

Sources

• Maraganore et al., JAMA 2006;296:661–670, DOI 10.1001/jama.296.6.661
• Cronin et al., Hum Mol Genet 2009;18:3274–3285, DOI 10.1093/hmg/ddp265 (abstract read)
• Not yet verified: follow-up in other ancestries; full text of the 2006 paper.