Perspectives
Genetics Neurology
Volume 208 - Issue 9

Identifying genes in Parkinson disease: state of the art

Authors:  Elaine GY Chew, Jia Nee Foo and Eng-King Tan

Med J Aust 2018; 208 (9): 381-382. || doi: 10.5694/mja17.01254
Published online: 21 May 2018

Recent studies are expanding our understanding of the genetic basis of Parkinson disease

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Recent studies are expanding our understanding of the genetic basis of Parkinson disease

Parkinson disease (PD) is a common neurodegenerative disorder which manifests as bradykinesia, movement rigidity and tremors in affected individuals. Our understanding of the genetic basis of PD has been steadily increasing since the initial report of α-synuclein mutations two decades ago.1 Mutations implicated in familial PD fully account for monogenic inheritance and point to potential functional mechanisms underlying PD.2,3 However, most sporadic PD cannot be accounted for by known familial PD genes, with the late-onset nature of PD making further linkage studies challenging. Genome-wide association and whole exome sequencing studies have implicated a growing list of mutations and genes in PD, which are expected to provide new insights into potential pathways involved in PD pathogenicity.

A meta-analysis of genome-wide association studies4 conducted across the largest cohort of PD patients and controls to date has identified 17 novel genome-wide significant risk loci, bringing the total number of PD-associated loci to 40.5,6 Although this has improved confidence for PD risk prediction in pre-symptomatic individuals, the confidence level is still too low to be suitable for clinical applications. Further genetic studies in larger patient cohorts are required to uncover not only common variants with increasingly small effect sizes but also increasingly rare variants that may have larger effect sizes, which may in turn improve genetic risk prediction scores. The presence of neurocentric candidate genes at these 17 novel loci confirmed the importance of lysosomal pathway regulation in PD. Of note, Robak and colleagues7 independently reported increased burden of non-synonymous and deleterious variants in lysosomal storage disorder genes in patients with PD, even when the well-established GBA variants were disregarded. The implication of lysosomal pathway genes in PD point towards lysosome involvement in α-synuclein degradation, supporting the use of current therapeutics which target lysosomal regulatory mechanisms to attenuate α-synuclein accumulation in PD patients.

As genome-wide association studies can only robustly assess common single nucleotide polymorphism, the discovery of novel and rare PD variants requires genomic sequencing approaches. Whole exome sequencing studies in Finnish8 and European9 populations have identified a total of 33 novel candidate genes for early-onset PD. Siitonen and colleagues8 (185 patients with PD and 440 controls) uncovered three novel exome-wide and statistically significant low penetrance PD candidate genes (MPHOSPH10, SERPINA1, TAS2R19). Further confirmation in larger datasets is needed for the small effect size variants identified in this low powered analysis. Jansen and colleagues9 (1148 patients with PD and 503 controls) identified 27 high penetrance PD genes with rare recessive loss-of-function variants from mostly single observations of homozygotes or compound heterozygotes, seven of which could be replicated in an independent cohort. Potential functional roles of variants were assessed via mitochondrial morphology changes and α-synuclein-mediated toxicity after knockdown of selected PD variant-harbouring genes; however, the exact functional implications in PD remain unclear. More genetic evidence, such as replication in diverse populations, should be accrued before further effort is placed into elucidating the precise PD-related functions of these candidate genes. While the approach adopted by Jansen and colleagues is feasible for preliminary functional validation of high penetrance loss-of-function variants, alternative methods may be needed for low penetrance PD variants.

Studies involving whole exome sequencing accompanied by linkage in families have continued to identify novel PD candidate genes and mutations, such as EIF4G1,10 VPS35,11 DNAJC1312 and, more recently, CHCHD213 and TMEM230.14 However, the implication of some of these genes in PD is still unclear and sometimes contentious. For example, the implication of TMEM230 in PD is currently being debated, with opposing findings from different groups.15,16 A follow-up study in a larger dataset refuted any major involvement of EIF4G1 in sporadic PD in both European and Asian populations.17 This emphasises the need for replication and validation of newly discovered genes and variants in large numbers of patients.

Overall, mutations and genes identified by whole exome sequencing in case–control studies and families appear to be extremely rare and account for a very small fraction of PD cases, thus highlighting the extreme genetic heterogeneity underlying PD. Further, the identification of 22q11.2 deletions in sporadic PD cases18 and the report of early onset PD in a small fraction of deletion carriers19 add further to the phenotypic and genotypic complexity of the disease. Statistically, very large numbers of samples (> 10,000) will be needed to provide sufficient statistical power to confirm the involvement of each gene or variant in PD. Comprehensive network or pathway analyses are necessary to assess how seemingly diverse genes and mutations lead to a common disease outcome. It is also increasingly important to develop and validate in vitro and in vivo models of variants identified by genome-wide association studies and exome or genome sequencing. Recent developments in the derivation of midbrain organoids from human pluripotent stem cells20 and neuroepithelial stem cells21 provide exciting prospects for modelling the effects of genetic variants in vitro as well as conducting compound screens for drug development.

All large-scale genetic studies on PD to date have been carried out in European populations. Studies of the PD G2019S risk variant in LRRK2,22 which is rare or absent in the Asian population, and the PD N370S and L444P risk variants in GBA,23 which are enriched in Ashkenazi Jews, have shown that disease risk variants may not be similarly implicated in PD across populations. Therefore, the validation of both common and rare risk variants across diverse populations is necessary. Variant discovery in non-European datasets is similarly important in unravelling the underlying genetic basis of PD across populations.

It is increasingly clear from the genetic findings of diverse PD risk factors among different populations and patient-specific mutations that PD is not a single disease with a single treatment approach. Instead, treatments should be tailored according to clinical and mutation or risk variant profile, and require systematic precision medicine approach.24 Pharmacogenetics should also be considered, as drug metabolism influences treatment strategies.25

It is important to note that the genetic findings thus far are germline variants that were detected in biological materials collected from non-invasive, non-pathogenic sites such as lymphocytes from peripheral blood. However, there is increasing awareness that somatic mutations that arise during development or accumulate with age26,27 at the site of disease pathology28,29 may also account for some sporadic cases of PD. These mutations are only detectable in post-mortem brain tissue and therefore are not useful for diagnostics or risk prediction, but could nevertheless point to potential novel pathways and druggable targets. Further, current sequencing approaches to detect rare variants focus on coding regions and leave out variants at non-coding regulatory regions. Future efforts should also be directed at deciphering the epigenetic landscape of PD30,31 to enable a system-based understanding of the condition.

There are two major challenges in the quest to identify underlying genetic factors in PD to date. First, large cohorts of PD patients and samples are required to detect increasingly rare variants with potentially smaller effect sizes. Second, there is a lack of comprehensive patient clinical data to associate with genetic data. PD is extremely heterogeneous, and patient cohorts may encompass individuals with similar PD-associated symptoms but a different underlying genetic basis; for example, 22q11.2 deletions. Comprehensive clinical data will greatly help delineate patients for genetic analysis. Analysis of genetic association together with longitudinal patient clinical data is crucial for the dissection of differences in drug response and disease progression with respect to PD-associated variants.

In summary, recent studies demonstrate an important step towards large collections of patients with PD for genetic studies. It is clear that the genetic basis underlying PD is highly heterogeneous and potentially population-specific, thus there are limitations to current approaches and much remains to be discovered. The discovery of highly penetrant genetic variants will be increasingly important in the genetic counselling of patients and family members as we accrue greater understanding of their mechanistic implications in PD. Potential PD treatment approaches explored currently, such as ambroxol to reduce GBA variant-associated α-synuclein accumulation,32 and small molecule inhibitors against LRRK2,33 have been informed by genetic findings. Comprehensive analysis of PD genetic variants is expected to point us towards more drug targets for PD treatment and management. Concerted efforts should therefore be directed at discovering additional PD variants and replicating existing ones in large cohort sizes and across diverse populations with longitudinal follow-up, which is only possible through international collaborations and consortium work. Functional validation in vitro and in vivo will improve the capability to further mine the enormous amount of genomic data that will define the future of genomic and precision medicine.

Authors

  • Elaine GY Chew1
  • Jia Nee Foo1,2
  • Eng-King Tan3,4
  • 1. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
  • 2. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
  • 3. National Neuroscience Institute, Singapore
  • 4. Duke–NUS Medical School, Singapore

Correspondence: tan.eng.king@singhealth.com.sg

Competing interests

No relevant disclosures.

Acknowledgements

Eng-King Tan acknowledges funding from the National Medical Research Council Singapore under the Singapore Translational Research Investigator Award and the Translational and Clinical Research Flagship Programme (NMRC/TCR/013-NNI/2014); Duke–NUS Medical School; and the Singapore Millennium Foundation. Jia Nee Foo is a Singapore National Research Foundation Fellow (NRF-NRFF2016-03).

References

Provenance: Commissioned; externally peer reviewed.

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