The genetic architecture of Parkinson's disease in Morocco: highlighting a predominance of Mendelian genes

Abstract

Background: Parkinson's disease (PD), although widely heterogeneous and manifesting with numerous motor and non-motor symptoms, presents clinically as a single entity worldwide. Its genetic causes are also heterogeneous and include highly penetrant variants in a single gene representing rare monogenic forms, and rare or common variants conferring a relative disease risk representing more frequent multigenic forms. Most of these variants have been discovered in patients of European ancestry. Since the genetic basis of PD can vary significantly between populations due to differences in allele frequencies, little is known about the genetics of PD in other populations, particularly from Africa. Morocco, located in a region of North Africa, constitutes a subcontinent known for a weak external genetic influence and for a local genetic continuity for millennia, which makes it a region of interest to study the genetic causes of PD.

Summary: This review aims to summarize published research data on the genetic profile of PD patients from the Moroccan population to describe its genetic architecture. Unlike in Western countries, Parkinson's disease in Morocco is predominantly a Mendelian disease reaching up to 50%, due to the high prevalence of the LRRK2 G2019S dominant variant and to relatively less frequent PRKN and PINK1 recessive variants due to the high rate of consanguinity. Additionally, rare high-risk variants in LRRK2, VPS13C, MAPT, and POLG, in oligo- or polygenic ways, may contribute to increasing the genetic risk of the disease.

Key messages: We therefore show that the genetic architecture of PD in Morocco, a country in the subcontinent of North Africa, was different from that of sub-Saharan Africa and the rest of the world. This will help improve diagnostic accuracy, subdivide the clinical variability of the disease into groups of common genetic and biological causes for a better therapeutic management strategy, and test molecules from ongoing clinical trials.

Fig. 1.

Prevalence of the LRRK2 G2019S mutation among 211 Moroccan PD patients.

Fig. 2.

Frequencies of high-risk variants identified in Mendelian genes alone, and concomitantly between risk factor and Mendelian genes found in Moroccan PD patients. The blue bar represents patients who have exclusively 2 rare high-risk variants in Mendelian genes with autosomal recessive inheritance. Yellow bars represent patients who have 2 to more than 4 high-risk rare variants in Mendelian genes and risk factors simultaneously.

Fig. 3.

Pie plot showing the genetic architecture of PD in Moroccan cohort. In this North African population, 38% of PD patients carry the pathogenic LRRK2 p.G2019S mutation, 10% carry a biallelic pathological variant in the known recessive PD genes, 28% have one or more rare high-risk variants, and finally, 24% do not have such variants in the twenty PD genes analyzed.