LARGE-PD Latino GWAS

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

The Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD). First author Douglas Loesch (University of Maryland); senior author Ignacio Mata (Cleveland Clinic, then University of Washington/VA Puget Sound); with 23andMe for replication. The paper reports nine clinical sites across South America; the 2025 follow-up names Brazil, Chile, Colombia, Peru and Uruguay for this first phase. Funding listed in the paper's records: NINDS (R01 NS112499), NHGRI (R35 HG010692), NHLBI (T32 HL007698), a Parkinson's Foundation International Research Grant and the Universidad de Antioquia.

What happened

The 2019 study of about 90 risk signals (landmark 19) used people of European ancestry. LARGE-PD asked whether the same genes drive disease in people of mixed Native American, European and African ancestry.

• Discovery. 1,497 people (807 cases, 690 controls, per the preprint). Average ancestry in the preprint was about 47% Amerindian and 47% European, about 5% African, but it varied by site.
• Replication. 23andMe tested top hits in 1,234 Hispanic/Latino cases and 439,522 controls.
• Findings. Only the SNCA region reached genome-wide significance. The lead variant rs356182 passed in both the discovery sample (G allele, odds ratio 1.58, p = 2.5 x 10^-8) and 23andMe (odds ratio 1.26, p = 4.6 x 10^-8). Admixture mapping (testing stretches of ancestry rather than single variants) flagged a chromosome 14 locus containing STXBP6 (joint and Native American tests) and a chromosome 6 locus containing RPS6KA2 (African-ancestry test), both only at p < 5 x 10^-5 and described as "potential". The preprint also reported a suggestive signal near NRROS and 80% concordance in direction of effect with the 2019 European variants; neither appears in the published abstract.
• Published in Annals of Neurology 2021;90:353–365 (DOI 10.1002/ana.26153; PMID 34227697; online 22 July 2021); preprint November 2020. Two short comments on it were published (Ann Neurol 90:350–352; Mov Disord 36:2505). No correction or retraction is recorded.
• Later work. A July 2025 medRxiv preprint (first author Thiago Leal, senior author Mata) added a replication phase of 4,401 samples (2,744 cases, 1,559 controls) from 10 countries and 23 sites. It found SNCA again (rs356182, odds ratio 1.52) and a new locus, ITPKB (lead variant rs117185933, odds ratio 1.75, p = 3.8 x 10^-12). Funders listed include NIH, ASAP's Global Parkinson's Genetics Program and the Michael J. Fox Foundation. The page says it has not been peer reviewed, and I found no journal version.

Why it moved us toward a cure

SNCA, the synuclein gene (landmark 4), is risk in a very different population, supporting synuclein as a universal target. The ITPKB hint, if confirmed, shows ancestry-specific biology that European-only maps miss. See also the multi-ancestry work in landmark 124, which came later.

ASAP's 2025 review describes LARGE-PD as the largest Latin American genome-wide study of Parkinson's, across 15 countries, reporting variants at SNCA and ITPKB (ASAP Year in Review 2025; the preprint itself lists 10 countries in the replication phase, so the figures differ).

Outcome

Advanced: it widened the genetic map and led to a larger follow-up.

Sources

• Loesch et al., Ann Neurol 2021, DOI 10.1002/ana.26153 (abstract and funding records read via Europe PMC)
• medRxiv preprint, Nov 2020 (807 cases, 690 controls, NRROS, 80% concordance; abstract read via Europe PMC)
• LARGE-PD 2025 preprint, PMC12338945
• ASAP Year in Review 2025
• Not yet verified: the claim in the MJFF 2020 Year in Review that the Foundation funded the 2020 expansion (no grant page found; the MJFF is not among the funders in the 2021 paper's records); whether the 2020 ancestry percentages and the 807/690 split are unchanged in the published paper; the consortium's founding year.