Objective: To investigate the association of hand preference with Parkinson’s disease (PD) (1) in a large prospective cohort study and (2) through a Mendelian randomization (MR) approach.

Background: A greater risk of PD in left-handed women was previously reported in the prospective Nurses’ Health Study but replication studies are lacking.[1]  Some genetic variants associated with left-handedness in previous genome-wide association studies (GWAS) are involved in the pathogenesis of neurological diseases.[2]

Method: Women 40-65 years old were enrolled in 1990 in the French E3N cohort study (N=98,995) and followed until 2018 through biennial questionnaires and drug claims.[3,4] PD was ascertained through expert validation of medical records or an algorithm based on antiparkinsonian drugs. Cox proportional hazard models with age as time-scale were used to investigate the association between left-handedness and PD incidence. A two-sample MR analysis (random-effects inverse-variance-weighted method) was performed using summary statistics for SNP-left hand preference associations from a published GWAS and SNP-PD associations from the International Parkinson Disease Genomic Consortium.[5,6]

Results: 69,025 women with hand preference information and without PD at inclusion were included in the study, and 816 incident PD cases were identified over a total time-at-risk of 1,909,078 person-years. Left-hand preference was reported by 1776 women (2.6%) and was associated with ~50% greater PD incidence (hazard ratio=1.52, 95% confidence interval [95%CI]=1.04-2.21; p=0.03). After exclusion of a pleiotropic SNP in the MAPT (microtubule-associated protein tau) locus on chromosome 17 (rs55974014) strongly associated with both hand preference and PD (p=3·10^-30 and 2·10^-27, respectively), the MR analysis was based on 31 independent SNPs associated with left handedness (p<5·10^-8) and found no significant association between left handedness and PD (odds ratio=0.88, 95%CI=0.62-1.26; p=0.50).

Conclusion: Our observational findings provide evidence of an association between left handedness and PD in women, confirming previous research.[1] The MR analysis, however, is not in favour of a causal association. Common biological mechanisms may be involved (e.g., pleiotropic genes, epigenetic changes), and further studies are needed to understand the link between hand preference and PD.

References: 1. Gardener H, Gao X, Chen H, Schwarzschild MA, Spiegelman D, Ascherio A. Prenatal and early life factors and risk of Parkinson’s disease. Mov Disord. 2010;25(11):1560-1567. doi:10.1002/mds.23339
2. Wiberg A, Ng M, Al Omran Y, et al. Handedness, language areas and neuropsychiatric diseases: insights from brain imaging and genetics. Brain. 2019;142(10):2938-2947. doi:10.1093/brain/awz257
3. Clavel-Chapelon F; E3N Study Group. Cohort Profile: The French E3N Cohort Study. Int J Epidemiol. 2015;44(3):801-809. doi:10.1093/ije/dyu184
4. Canonico M, Artaud F, Degaey I, et al. Incidence of Parkinson’s disease in French women from the E3N cohort study over 29 years of follow-up. Eur J Epidemiol. 2022, https://doi.org/10.1007/s10654-022-00851-y
5. Cuellar-Partida G, Tung JY, Eriksson N, et al. Genome-wide association study identifies 48 common genetic variants associated with handedness. Nat Hum Behav. 2021;5(1):59-70. doi:10.1038/s41562-020-00956-y
6. Desikan RS, Schork AJ, Wang Y, et al. Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus. Mol Psychiatry. 2015;20(12):1588-1595. doi:10.1038/mp.2015.6

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MDS Abstracts - https://www.mdsabstracts.org/abstract/is-left-handedness-associated-with-parkinsons-disease-evidence-from-the-e3n-cohort-study-and-mendelian-randomization/