rs34637584

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This is a variant in the LRRK2 gene that changes a glycine to an serine.

Key Literature Trait Associations

Parkinson's Disease

The LRRK2 G2019S variant (rs34637584-A) is the most common pathogenic mutation causing both familial and sporadic Parkinson's disease. In a landmark GWAS meta-analysis of over 1.4 million participants (Nalls et al., 2019, Lancet Neurology), the variant achieved a p-value of 4×10⁻¹⁴⁸ with a beta of 2.43. Odds ratios from earlier studies range from ~7.5 to 9.6. Penetrance is age-dependent and ancestry-specific: a meta-analysis of 49 studies (Trinh et al., 2014, JAMA Neurology) found cumulative incidence reaches ~24% in Ashkenazi Jews by age 80, with higher estimates in North African Arab carriers. The mutation accounts for 13–40% of familial PD in Ashkenazi and North African populations and 1–2% of sporadic PD in Europeans.

Nalls MA et al. “Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.” The Lancet. Neurology 18(12):1091-1102 (2019)
Allele A
OR —
β 2.429 ±0.094
p 4.0e-148
N 1,474,097
Meta-analysisLarge GWAS
European
Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele A
OR —
β 1.594
p 7.0e-17
N 630,290
Major Consortium StudyLarge GWAS
multi-ancestry
Do CB et al. “Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.” Plos Genetics 7(6):e1002141 (2011)
Allele A
OR 9.62
p 2.0e-28
N 33,050
Large GWAS
European
Trinh J et al. “Disease penetrance of late-onset parkinsonism: a meta-analysis.” Jama Neurology (2014)
Allele A
OR —
p —
N 709
Meta-analysis
multi-ancestry
Lesage S et al. “G2019S LRRK2 mutation in French and North African families with Parkinson's disease.” Annals of Neurology (2005)
Allele A
OR —
p —
N 198
Candidate gene study
North African / European

Cognitive impairment in Parkinson's disease

A systematic review by D'Souza & Rajkumar (2020, Acta Neuropsychiatrica) of 43 articles found that LRRK2 G2019S minor allele (A) carriers had significantly less cognitive impairment compared to non-carriers among PD patients (p=0.015). This suggests that LRRK2-associated PD may have a relatively benign cognitive trajectory compared to idiopathic PD, which has been corroborated by clinical observations that LRRK2 G2019S carriers show typical PD motor phenotype without excess dementia risk. The G allele (reference) is thus coded here as the risk allele for cognitive impairment in PD.

D'Souza T et al. “Systematic review of genetic variants associated with cognitive impairment and depressive symptoms in Parkinson's disease.” Acta Neuropsychiatrica (2020)
Allele G
OR —
p 1.5e-2
Candidate gene study
multi-ancestry

Levodopa-induced dyskinesia

A systematic review and meta-analysis by Falla et al. (2021, Parkinsonism & Related Disorders) pooling 33 studies in 27,092 subjects found no statistically significant association between rs34637584 (LRRK2 G2019S) and susceptibility to levodopa-induced dyskinesia (LID) in Parkinson's disease patients. LRRK2 G2019S carriers generally display clinical PD features indistinguishable from idiopathic PD and have similar levodopa responsiveness, but the variant does not appear to independently predict LID development. This null finding is itself clinically informative for counseling carriers about expected treatment response.

Falla M et al. “Genetic variants in levodopa-induced dyskinesia (LID): A systematic review and meta-analysis.” Parkinsonism & Related Disorders (2021)
Allele A
OR —
p —
N 27,092
Meta-analysis
multi-ancestry
▶

GWAS Catalog Trait Associations (1)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

Parkinson disease

Nalls MA et al. “Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.” The Lancet. Neurology 18(12):1091-1102 (2019)
Allele A
OR 2.43
p 4.0e-148
N 482,730
Meta-analysisLarge GWAS
European
Doostparast Torshizi A et al. “Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson's disease.” Nature Communications 15(1):6430 (2024)
Allele A
OR 2.27
p 7.0e-12
N 539,017
Large GWAS
European
Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele A
OR 1.80
p 3.0e-12
N 400,487
Major Consortium StudyLarge GWAS
multi-ancestry
Do CB et al. “Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.” Plos Genetics 7(6):e1002141 (2011)
Allele A
OR 9.62
p 2.0e-28
N 33,050
Large GWAS
European
▶

ClinVar annotation

Pathogenic★★★☆
29 submitters69 publications

Autosomal dominant Parkinson disease 8; Inborn genetic diseases; LRRK2-related disorder; Parkinson disease (PD); Parkinson disease, late-onset (PD); Young-onset Parkinson disease

View on ClinVar →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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