A risk variant that regulates SNCA

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

Frank Soldner and Rudolf Jaenisch (Whitehead Institute, MIT), with Richard Young, Yonatan Stelzer, Brian Abraham, Jeanne Latourelle and Richard Myers (10 authors). Jaenisch's part was paid by US National Institutes of Health grants and a Qatar National Research Fund grant.

What happened

Genome-wide studies (landmark 19 is the later, larger one) had found common DNA variants near the synuclein gene (SNCA) that raise Parkinson's risk slightly, but these lie outside the protein-coding part, so how they act was unclear. Soldner's team combined maps of regulatory DNA ("epigenetic" data) with CRISPR/Cas9 genome editing in human pluripotent stem cells, so that the same genetic background differed only at the variant. They identified a common risk variant, rs356168, in an enhancer inside intron 4 of SNCA (a DNA stretch that can raise a gene's activity). Inserting the enhancer with the risk (G) allele raised SNCA expression; the A allele had no effect compared with a deleted enhancer. The authors call the effect modest and life-long. In 127 post-mortem frontal cortex samples (86 Parkinson's, 41 controls) total SNCA was higher in carriers of the risk allele (p=0.031). The variant was associated with sequence-dependent binding of two brain-specific transcription factors, EMX2 and NKX6-1. Nature 533:95–99, 20 April 2016.

Why it moved us toward a cure

It showed how common inherited risk can act: not by changing the protein but by changing how much is made, matching the lesson of the triplication families that extra synuclein is enough to cause disease (landmark 14). It is consistent with lowering synuclein production as a strategy for many patients, not only rare families (landmark 29), and it gave a method for working out other risk variants.

The work relied on gene-edited, matched stem-cell lines (landmark 272).

An earlier common SNCA variant, the Rep1 repeat in the gene's control region, had been linked to risk in 2006 (landmark 334).

Outcome

Open. One variant at one locus was dissected; the effect on risk of the other ~90 signals (landmark 19) is not resolved by this work, and no therapy has been built on it. A 2022 study from Riess's group (Cheng et al., Science Advances) found that the intronic enhancers of SNCA act mainly in brain and are controlled by THAP1 and CTCF, with Parkinson's-linked variants enriched there. That is related, not a direct replication of rs356168. No correction or retraction was found; two Nature/Mov Disord comment pieces accompanied the paper.

Sources

• Soldner et al., Nature 2016;533:95–99, DOI 10.1038/nature17939, PMID 27096366 (abstract via Europe PMC; full text via MIT DSpace and PMC5042324)
• Cheng et al., Sci Adv 2022;8, DOI 10.1126/sciadv.abq6324, PMID 36417521
• Not yet verified: whether independent labs reproduced the rs356168 allele effect itself; any drug designed around the enhancer.