Objective: To expand upon previous work assessing the prevalence of the LRRK2 p.Q1111H variant in Latin America and implement local ancestry analysis to assess ancestral specificity of the variant.

Background: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene account for most familial Parkinson’s disease (PD) cases, as well as a significant proportion of sporadic cases [1,2]. In 2007, Nichols et al. identified five novel LRRK2 variants associated with PD, including p.Q1111H (rs78365431), which was found in two Hispanic brothers [3]. 

A follow up study with the Latin American Research consortium on the Genetics of PD (LARGE-PD) investigating the prevalence of the variant in four Latin American countries identified the variant in both affected and unaffected individuals, with no significant difference in the frequency [4]. The variant was hypothesized to have originated in a Native American population; however, this was based on self-reported ancestry and no ancestry analyses were performed.

Method: All samples (n=4,307) were genotyped using the NeuroBoster Array [5]. Genotypes were called using the Illumina Array Analysis Platform. We performed genotyping quality control using the LARGE-PD GWAS QC pipeline (https://github.com/MataLabCCF/GWASQC).

We performed local ancestry (LA) inference using G-Nomix [6]. The reference panel was composed of African (AFR), European (EUR), and Native American (NAT) samples from the 1000 Genomes Project [7]. An additional 158 LARGE-PD samples with NAT ancestry ≥ 99.99% were added to the panel to boost sample size.

Results: Across the cohort, 6.15% of affected individuals (n=2,747), 18.7% of controls (n=1,560), and 10.7% of total participants were carriers of the “H” allele (p=0.4). The country with the largest percent of carriers per sample size was Peru (n=1,291, carriers=25.8%), followed by Chile (n=489, carriers=9.2%). Peru was also the only country with homozygous carriers.

The LA analysis revealed 97.93% of carriers had NAT ancestry in the window that contains the variant, 2.07% had EUR ancestry, and no carriers had AFR ancestry. Additionally, 11.2% of all individuals with NAT ancestry in the window were also carriers.

Conclusion: Our results support the hypothesis that the LRRK2 p.Q1111H variant is not pathogenic for PD, and that the variant likely originated from a NAT ancestry population.

References: [1] Paisán-Ruı́z, C., Jain, S., Evans, E. W., Gilks, W. P., Simón, J., van der Brug, M., de Munain, A. L., Aparicio, S., Gil, A. M., Khan, N., Johnson, J., Martinez, J. R., Nicholl, D., Carrera, I. M., Peňa, A. S., de Silva, R., Lees, A., Martı́-Massó, J. F., Pérez-Tur, J., … Singleton, A. B. (2004). Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson’s Disease. Neuron, 44(4), 595–600. https://doi.org/10.1016/j.neuron.2004.10.023
[2] Usmani, A., Shavarebi, F., & Hiniker, A. (2021). The Cell Biology of LRRK2 in Parkinson’s Disease. Molecular and Cellular Biology, 41(5), e00660-20. https://doi.org/10.1128/MCB.00660-20
[3] Nichols, W. C., Elsaesser, V. E., Pankratz, N., Pauciulo, M. W., Marek, D. K., Halter, C. A., Rudolph, A., Shults, C. W., Foroud, T., & Parkinson Study Group-PROGENI Investigators. (2007). LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. Neurology, 69(18), 1737–1744. https://doi.org/10.1212/01.wnl.0000278115.50741.4e
[4] Mata, I. F., Wilhoite, G. J., Yearout, D., Bacon, J. A., Cornejo, M., Mazzetti, P., Marca, V., Ortega, O., Acosta, O., Cosentino, C., Torres, L., Medina, A. C., Perez-Pastene, C., Díaz-Grez, F., Vilariño-Güell, C., Venegas, P., Miranda, M., Trujillo-Godoy, O., Layson, L., … Ross, O. A. (2011). Lrrk2 p.Q1111H substitution and Parkinson’s disease in Latin America. Parkinsonism & Related Disorders, 17(8), 629–631. https://doi.org/10.1016/j.parkreldis.2011.05.003
[5] Bandres-Ciga S, Faghri F, Majounie E, Koretsky MJ, Kim J, Levine KS, Leonard H, Makarious MB, Iwaki H, Crea PW, Hernandez DG, Arepalli S, Billingsley K, Lohmann K, Klein C, Lubbe SJ, Jabbari E, Saffie-Awad P, Narendra D, Reyes-Palomares A, Quinn JP, Schulte C, Morris HR, Traynor BJ, Scholz SW, Houlden H, Hardy J, Dumanis S, Riley E, Blauwendraat C, Singleton A, Nalls M, Jeff J, Vitale D; Global Parkinson’s Genetics Program (GP2) and the Center for Alzheimer’s and Related Dementias (CARD). NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations. Mov Disord. 2024 Nov;39(11):2039-2048. doi: 10.1002/mds.29902. Epub 2024 Sep 16. PMID: 39283294; PMCID: PMC11568947.
[6] Hilmarsson, H., Kumar, A. S., Rastogi, R., Bustamante, C. D., Montserrat, D. M., & Ioannidis, A. G. (2021). High Resolution Ancestry Deconvolution for Next Generation Genomic Data (p. 2021.09.19.460980). bioRxiv. https://doi.org/10.1101/2021.09.19.460980
[7] Byrska-Bishop, M., Evani, U. S., Zhao, X., Basile, A. O., Abel, H. J., Regier, A. A., Corvelo, A., Clarke, W. E., Musunuri, R., Nagulapalli, K., Fairley, S., Runnels, A., Winterkorn, L., Lowy, E., Human Genome Structural Variation Consortium, Paul Flicek, null, Germer, S., Brand, H., Hall, I. M., … Zody, M. C. (2022). High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios. Cell, 185(18), 3426-3440.e19. https://doi.org/10.1016/j.cell.2022.08.004

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MDS Abstracts - https://www.mdsabstracts.org/abstract/prevalence-and-local-ancestry-of-lrrk2-p-q1111h-in-latin-american-cohort/