Lack of full sequencing gba1 studies for patients with parkinson’s disease in latin america

ABSTRACT Full sequencing of the _GBA1_ gene in patients with Parkinson’s disease provides a wide screening of pathogenic variants, but less developed regions of the world, like Latin

America, may have difficulties in performing full sequencing. We performed a systematic review with meta-analysis to explore the prevalence and the odds ratio of specific _GBA1_ variants in

Parkinson’s disease in Latin America. We noted a lack of full sequencing _GBA1_ studies in Latin America. SIMILAR CONTENT BEING VIEWED BY OTHERS EXOME SEQUENCING IN ASIAN POPULATIONS

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access 27 June 2023 Variants in the _GBA1_ gene are strong genetic risk factors for developing sporadic Parkinson’s disease (PD). Some of these variants (p.N370S, p.L444P, and p.E326K) have

high allelic frequencies in patients with PD and increased risk for developing the disease1,2. The prevalence of _GBA1_ variants in Ashkenazi Jewish populations with PD is the highest (18%)

compared to other ethnic backgrounds1. In non-Ashkenazi patients with PD, the prevalence of _GBA1_ variants is close to 10%, but it may vary according to the country and screening

methodology. For _GBA1_ analysis, most studies use genotyping methods targeting specific common pathogenic variants or sequencing3. _GBA1_ is a large gene located in a complex genomic

region, with a pseudogene with 96% of homology in the coding sequence, which increases the risk of recombination and poses challenges to PCR and sequencing. Regarding _GBA1_ sequencing,

while some studies opted for sequencing and analyzing all exons (full sequencing), other groups are sequencing only specific exons, like exons 9 and 10, where common variants are found

(targeted sequencing)3. Recently, long-read sequencing methods have been employed to study better the region4. The full sequencing of _GBA1_ warrants the identification of rare or

population-specific variants, shedding light on the pathophysiology of effects of _GBA1_ in PD and helping to recruit more eligible patients for _GBA1_-targeted trials5. In Latin America, a

region with a population of approximately 660 million, few studies on PD associated with _GBA1_ variants (PD-_GBA_) have been published. Latinos, referring to those individuals from Latin

America, are genetically very heterogeneous due to a complex three-way admixture (Native American, European and African), with large differences in the amounts of each ancestry not only

between but also within countries. Furthermore, unfavorable socioeconomic conditions among its countries may hamper the capacity to perform the full sequencing of _GBA1_, which may

negatively influence the results of these studies. To explore the prevalence and odds ratio of PD-_GBA_ in Latin America, we conducted a systematic literature review and meta-analysis. A

total of 11 clinic-based studies (one study was conducted in two different countries, comprising 12 cohorts) were included in the analysis (Supplementary Fig. 1). A total of 1,719 patients

with PD and 1,444 controls were analyzed, and an average prevalence of 5.4% of _GBA1_ carriers was found (Table 1). No participant reported Ashkenazi Jewish ancestry. There are some

methodological differences among studies: four studies recruited only early-onset patients with PD (age at onset varying from less than 45 to less than 55 years), and two studies did not

include healthy controls. Only four cohorts performed full sequencing of _GBA1_ (n patients = 735; n controls = 445). Despite Brazil being the most populous country in Latin America and with

more patients with PD screened for _GBA1_ variants, surprisingly no study from this country used full sequencing of the gene. We performed a meta-analysis to estimate the odds ratio (OR) of

developing PD for carriers of all pathogenic _GBA1_ variants plus p.E326K, and specifically for carriers of p.L444P and p.N370 variants. We used a fixed-effect model with a continuity

correction of 0.5 for studies with zero _GBA1_ carriers in the PD or control group. For calculating the OR, we used the Cochran–Mantel–Haenszel test and the Tarone test to examine

heterogeneity6. Statistical tests were performed using the R software version 4.0.4, with the package _metafor_. In the meta-analysis to estimate the OR of all pathogenic _GBA1_ variants

(p.L444P, p.N370S, p.K198E, IVS2 + 1 G > A, _Rec1_) plus p.E326K, we used only studies which performed full sequencing, avoiding the underestimation of other methods of genetic screening.

Carrying any pathogenic _GBA1_ variant plus p.E326K was associated with an increased risk of PD (OR = 3.51, 95% CI = 1.6–7.4), but heterogeneity was significant (Tarone _p_ = 0.02). After

excluding the cohort with extreme OR (with two carriers of variants in controls, but none in patients with PD), the heterogeneity was removed (OR = 4.63, 95% CI = 1.9–10.7; Tarone _p_ = 

0.96; Fig. 1a). For p.L444P (combining full and targeted sequencing studies), the average allelic frequency was 0.028 in patients and 7.7 × 10−4 in controls; the variant increased

substantially the risk of PD (OR = 20.2, 95% CI = 3.4–118.9, Fig. 1b), and heterogeneity was not significant (Tarone _p_ = 0.39). For p.N370S (combining full and targeted sequencing

studies), the average allelic frequency was 0.012 in patients and 0.001 in controls; the variant increased the risk of PD (OR = 4.9, 95% CI = 1.2–19.8, Fig. 1c); however, the heterogeneity

was significant (Tarone _p_ = 0.02). We must highlight that the p.L444P variant causes a more severe form of Gaucher’s disease than p.N370S6. Only one study (including individuals from Peru

and Colombia) explored the effect of pathogenic variants of _GBA1_ on clinical phenotype (age at onset), and carriers had motor symptoms approximately eight years earlier than non-carriers7.

Until now, approximately 10,000 patients with PD have been full-sequenced for _GBA1_ in Europe5. The low proportion of variants in controls could be reduced with the full sequencing and

larger numbers of participants. The OR values calculated by our meta-analysis for combined pathogenic _GBA1_ variants plus p.E326K and p.N370S were similar to previous studies in

non-Ashkenazi populations (Supplementary Table 1). However, the overall OR for p.L444P in Latin America was one of the highest values in non-Ashkenazi populations (Supplementary Table 1),

mainly due to studies from Brazil8,9,10,11,12,13 and Mexico14. We detected heterogeneity between studies, probably due to low numbers and distinct inclusion criteria (studies recruiting any

patients with sporadic PD, focusing on patients with early-onset PD or positive family history of PD). For example, we excluded the study from Costa Rica from the meta-analysis to reduce

heterogeneity. The study found no _GBA1_ variants in patients with PD, probably due to low sample size, the method of sequencing (molecular inversion probes), and a geographical enrollment

bias (participants from a specific metropolitan area, in the detriment of metropolitan areas and coastal zones of the country)15. Full sequencing of _GBA1_ in Latinos has already discovered

the pathogenic p.K198E variant in Colombia, with a prevalence of 6% in patients with PD, increasing the disease risk six-fold7, showing that some variants of clinical relevance may only be

reported after sequencing the whole gene. Thus, considering the results of our review, it remains unclear how much the full sequencing of _GBA1_ would increase the number of PD-associated

variants found compared to targeted approaches in Latin America. The number of studies that performed full sequencing of _GBA1_ is very low (four cohorts) and included a limited number of

patients compared to other populations. More large-scale studies in PD-_GBA_ using the full sequencing in Latin America are needed and may elucidate this issue. Promising ongoing clinical

trials on PD-_GBA_ may bring novel therapies for these patients; providing more _GBA1_ full-sequencing opportunities for Latin American populations would diminish health disparities for

underrepresented communities. METHODS We performed a search of PubMed/MEDLINE and EMBASE from inception until October 2021. We created search strings for each database using “Parkinson’s

disease,” “GBA,” and the countries in Latin America (Supplementary Table 2). Two rounds of study selection were performed. In the first round, we included original studies describing

patients with PD carrying _GBA1_ variants from all countries of Latin America. Reviews, meta-analyses, and studies with animal models were excluded. In the second round, full texts were

evaluated, and we selected articles that reported _GBA1_ genotyping (pathogenic variants plus p.E326K variant) or _GBA1_ sequencing on cohorts of patients with PD. Two reviewers performed

selection rounds independently, and disagreements were resolved by consensus. After, data were collected through an online spreadsheet. DATA AVAILABILITY The datasets generated and/or

analyzed during the current study are available from the corresponding author on reasonable request. Other data are available within the article or supplementary materials. REFERENCES *

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parkinsonism from Venezuela. _Mov. Disord._ 21, 282–283 (2006). Article  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Laboratory of Experimental

Neuropathology, Federal University of Pará, Belém, PA, Brazil Bruno Lopes Santos-Lobato * Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil Artur F. Schumacher-Schuh * Genomic

Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Ignacio F. Mata Authors * Bruno Lopes Santos-Lobato View author publications You can also search for this

author inPubMed Google Scholar * Artur F. Schumacher-Schuh View author publications You can also search for this author inPubMed Google Scholar * Ignacio F. Mata View author publications You

can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors have designed the study. B.L.S.-L. and A.F.S.-S. performed the systematic review. B.L.S.-L. analyzed data,

performed meta-analysis and wrote the first draft of the manuscript. All authors have revised the manuscript and approved the submission of the manuscript in its current form. CORRESPONDING

AUTHOR Correspondence to Bruno Lopes Santos-Lobato. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer

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Schumacher-Schuh, A.F. & Mata, I.F. Lack of full sequencing _GBA1_ studies for patients with Parkinson’s disease in Latin America. _npj Parkinsons Dis._ 8, 101 (2022).

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