Evidence map›Paper›PMID 40926580›Full record

Observational studyAnnals of clinical and translational neurology2025

Genetic Modifiers of Parkinson's Disease: A Case-Control Study.

Matthew J Kmiecik, Michael V Holmes, Pierre Fontanillas, Giulietta M Riboldi, Ruth B Schneider, Jingchunzi Shi, Anna Guan, Susana Tat, Steven Micheletti, Keaton Stagaman and 6 more

Abstract readObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in Annals of clinical and translational neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Matthew J Kmiecik23andMe, Inc., Sunnyvale, California, USA.ORCID https://orcid.org/0000-0001-5340-3872
Michael V Holmes23andMe, Inc., Sunnyvale, California, USA.
Pierre Fontanillas23andMe, Inc., Sunnyvale, California, USA.
Giulietta M RiboldiThe Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU Grossman School of Medicine, New York, New York, USA.ORCID https://orcid.org/0000-0003-0322-5718
Ruth B SchneiderUniversity of Rochester Medical Center, Rochester, New York, USA.
Jingchunzi Shi23andMe, Inc., Sunnyvale, California, USA.
Anna Guan23andMe, Inc., Sunnyvale, California, USA.
Susana Tat23andMe, Inc., Sunnyvale, California, USA.
Steven Micheletti23andMe, Inc., Sunnyvale, California, USA.
Keaton Stagaman23andMe, Inc., Sunnyvale, California, USA.
Josh GottesmanThe Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.
David A Hinds23andMe, Inc., Sunnyvale, California, USA.
Joyce Y Tung23andMe, Inc., Sunnyvale, California, USA.
23andMe Research Team
Stella Aslibekyan23andMe, Inc., Sunnyvale, California, USA.
Lucy Norcliffe-Kaufmann23andMe, Inc., Sunnyvale, California, USA.

Funding

Michael J. Fox Foundation for Parkinson's Research
6 · The paper itself

Abstract

objectiveTo examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms.

methodsWe conducted a US-based observational case-control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome-wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non-motor symptoms according to genetic exposure.

resultsBy the age of 80 years, the cumulative incidence of PD was 30% for dual carriers, 24% for LRRK2 p.G2019S carriers, 4% for GBA1 p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. GBA1 p.N409S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 p.G2019S with the lowest. APOE E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status.

interpretationOur findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.

Indexed as

GlucosylceramidaseLeucine-Rich Repeat Serine-Threonine Protein Kinase-2Parkinson DiseaseAgedAged, 80 and overApolipoprotein E4Case-Control StudiesFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMaleMiddle AgedMultifactorial InheritancePenetranceApolipoprotein E4GBA protein, humanGlucosylceramidaseLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LRRK2 protein, humanGBA1LRRK2neurodegenerationParkinson's diseasepolygenic risk scores

Identifiers

PMID40926580
PMCPMC12698958

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.