Abstract
Over the last decades, genetics has been the engine that has pushed us along on our voyage to understand the etiology of Parkinson’s disease (PD). Although a large number of risk loci and causative mutations for PD have been identified, it is clear that much more needs to be done to solve the missing heritability mystery. Despite remarkable efforts, as a field, we have failed in terms of diversity and inclusivity. The vast majority of genetic studies in PD have focused on individuals of European ancestry, leading to a gap of knowledge on the existing genetic differences across populations and PD as a whole. As we move forward, shedding light on the genetic architecture contributing to PD in non-European populations is essential, and will provide novel insight into the generalized genetic map of the disease. In this review, we discuss how better representation of understudied ancestral groups in PD genetics research requires addressing and resolving all the challenges that hinder the inclusion of these populations. We further provide an overview of PD genetics in the clinics, covering the current challenges and limitations of genetic testing and counseling. Finally, we describe the impact of worldwide collaborative initiatives in the field, shaping the future of the new era of PD genetics as we advance in our understanding of the genetic architecture of PD.
Highlights
Parkinson’s disease (PD) is a complex neurodegenerative disorder whose prevalence is predicted to increase drastically, being more pronounced in older age people and with variations among sex and ancestry groups [1]
The heritability of PD driven by common genetic variation is estimated to be ~22% and only approximately one third of it has been uncovered with the largest genetic study in the European ancestry population to date [2]
PD is a complex genetic disease, and such heritable genetic variation has a different magnitude of effect, frequency, deleteriousness, and penetrance, so that we can differentiate between rare or common variants, pathogenic deleterious mutations or variants that slightly increase the risk for developing PD, and incomplete versus complete penetrance [3]
Summary
Parkinson’s disease (PD) is a complex neurodegenerative disorder whose prevalence is predicted to increase drastically, being more pronounced in older age people and with variations among sex and ancestry groups [1]. PD is a complex genetic disease, and such heritable genetic variation has a different magnitude of effect, frequency, deleteriousness, and penetrance, so that we can differentiate between rare or common variants, pathogenic deleterious mutations or variants that slightly increase the risk for developing PD, and incomplete versus complete penetrance [3]. Genome wide association studies (GWAS) have been a powerful tool to better understand how genetics contribute to the risk, progression, and onset of PD [2,8,9]. A drawback of all the progress made in understanding PD genetics is that the vast majority of studies have focused on individuals of European ancestry, leading to a gap of knowledge on the likely existing genetic differences among populations. We provide an overview of the current state of the field and its applicability in clinical practice, as well as highlight the role of worldwide initiatives in shaping the future of the new era of PD genetics as we advance in our understanding of the genetic architecture of PD
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