Trends in Genetics
Volume 31, Issue 3, March 2015, Pages 140-149
Journal home page for Trends in Genetics

Review
Progress in unraveling the genetic etiology of Parkinson disease in a genomic era

https://doi.org/10.1016/j.tig.2015.01.004Get rights and content

Highlights

  • MPS accelerated the identification of genes for PD.

  • The use of MPS of gene panels has revolutionized genetic testing for PD.

  • Genome sequencing might overcome the pitfalls of genetic heterogeneity in complex PD.

Parkinson disease (PD) and Parkinson-plus syndromes are genetically heterogeneous neurological diseases. Initial studies into the genetic causes of PD relied on classical molecular genetic approaches in well-documented case families. More recently, these approaches have been combined with exome sequencing and together have identified 15 causal genes. Additionally, genome-wide association studies (GWASs) have discovered over 25 genetic risk factors. Elucidation of the genetic architecture of sporadic and familial parkinsonism, however, has lagged behind that of simple Mendelian conditions, suggesting the existence of features confounding genetic data interpretation. Here we discuss the successes and potential pitfalls of gene discovery in PD and related disorders in the post-genomic era. With an estimated 30% of trait variance currently unexplained, tackling current limitations will further expedite gene discovery and lead to increased application of these genetic insights in molecular diagnostics using gene panel and exome sequencing strategies.

Section snippets

PD and related disorders

Parkinsonism refers to a group of neurological syndromes presenting with bradykinesia, muscle rigidity, resting tremor, and postural instability. PD, the most common form of parkinsonism, is clinically characterized by these four cardinal motor symptoms as well as a good response to levodopa therapy [1]. Various nonmotor symptoms may present, including depression, sleep disturbances, constipation, orthostatic hypertension, and, in later disease stages, dementia [2]. Neuropathological hallmarks

Disentangling the genetic etiology

For many years, PD was considered a nongenetic disorder caused by synergistic environmental factors. A study estimating the heritability of PD risk in over 500 nuclear families revealed, however, that in up to 60% of idiopathic PD patients the phenotype could be explained by genetic factors [4]. Furthermore, this genetic etiology was shown to be significantly heterogeneous [5]. Currently, PD is considered a multifactorial disease involving numerous genetic and environmental factors.

Confounding factors in gene identification

Although substantial progress has been made toward the elucidation of the complex genetic etiology of PD and related disorders, it has been noticeably slow compared with pure Mendelian diseases. There are many confounding factors that contribute to this relatively slower rate of gene identification. We discuss below two classes of factors – technical and systemic – that present challenges for PD researchers.

Key molecular processes and therapeutic implementations

The identification of parkinsonism genes has been followed by intense molecular research indicating that neuronal death may originate from the interconnection of various processes including endosomal protein sorting and recycling, synaptic transmission, mitochondrial quality control, and lysosome-mediated autophagy. As discussed above, most of the recent gene discoveries converge on abnormal endocytosis and endosome trafficking as key pathomechanisms for PD and related disorders. Genetic

Translating genetic findings to the clinic

Molecular diagnostic testing encompasses systematic screening of patients and at-risk individuals for the presence of pathogenic, so far mostly exonic, variants in known causal genes. Diagnosing PD is not an exact science, as diagnostic accuracy rates at best reach 88% [119]. Molecular diagnoses may complement clinical diagnoses and consequently improve both diagnostic sensitivity and specificity, reducing the diagnostic uncertainty. Furthermore, it enables early diagnosis as well as prenatal

Concluding remarks

The pathological and genetic overlap between PD and Parkinson-plus syndromes suggests that expanding our knowledge of one disease entity might shed light on the other members of this disease continuum. Genetic commonalities have been observed, with MAPT, SNCA, and GBA variability contributing to susceptibility to different Parkinsonian disorders 39, 46, 47, 54, 63, 64, 65, 66. However, family-based gene identification studies and subsequent functional characterization of the encoded proteins

Acknowledgments

Research in the authors’ group is partly funded by the Belgian Science Policy Office Interuniversity Attraction Poles Program, the Flemish Government-initiated Methusalem Excellence program, the Alzheimer Research Foundation, Research Foundation Flanders (FWO), the Agency for Innovation by Science and Technology (IWT), and the University of Antwerp Research Fund, Belgium. A.V. receives a PhD fellowship from the IWT.

Glossary

Anticipation
progressively earlier appearance and increased disease severity in successive family generations, often present in families segregating STR expansions.
Candidate gene association studies
a case-control study in which genetic variation within a prespecified gene of interest is statistically compared.
Epigenetics
transient gene expression controllers that enable rapid biological adaptation, including CpG DNA methylation, post-translational histone modifications, and RNA-associated

References (133)

  • A.J. Parsian

    Association of α-synuclein gene haplotypes with Parkinson's disease

    Parkinsonism Relat. Disord.

    (2007)
  • G.D. Mellick

    Australian data and meta-analysis lend support for α-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease

    Neurosci. Lett.

    (2005)
  • O.A. Ross

    Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study

    Lancet Neurol.

    (2011)
  • M. Farrer

    The tau H1 haplotype is associated with Parkinson's disease in the Norwegian population

    Neurosci. Lett.

    (2002)
  • N. Tayebi

    Gaucher disease and parkinsonism: a phenotypic and genotypic characterization

    Mol. Genet. Metab.

    (2001)
  • N. Tayebi

    Gaucher disease with Parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism?

    Mol. Genet. Metab.

    (2003)
  • A. Lwin

    Glucocerebrosidase mutations in subjects with parkinsonism

    Mol. Genet. Metab.

    (2004)
  • D.C. Samuels

    Finding the lost treasures in exome sequencing data

    Trends Genet.

    (2013)
  • Y. Huang

    Anticipation of onset age in familial Parkinson's disease without SCA gene mutations

    Parkinsonism Relat. Disord.

    (2006)
  • Y.Q. Niu

    Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): revisited

    Parkinsonism Relat. Disord.

    (2014)
  • M.P. Socal

    Intrafamilial variability of Parkinson phenotype in SCAs: novel cases due to SCA2 and SCA3 expansions

    Parkinsonism Relat. Disord.

    (2009)
  • Y.Y. Tan

    Methylation of α-synuclein and leucine-rich repeat kinase 2 in leukocyte DNA of Parkinson's disease patients

    Parkinsonism Relat. Disord.

    (2014)
  • D.J. Gelb

    Diagnostic criteria for Parkinson disease

    Arch. Neurol.

    (1999)
  • T.H. Hamza et al.

    The heritability of risk and age at onset of Parkinson's disease after accounting for known genetic risk factors

    J. Hum. Genet.

    (2010)
  • J.S. Moilanen

    Complex segregation analysis of Parkinson's disease in the Finnish population

    Hum. Genet.

    (2001)
  • K. Nuytemans

    Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update

    Hum. Mutat.

    (2010)
  • J. Trinh et al.

    Advances in the genetics of Parkinson disease

    Nat. Rev. Neurol.

    (2013)
  • E.C. Schulte

    Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease

    Neurogenetics

    (2012)
  • J. Huttenlocher

    EIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts

    J. Med. Genet.

    (2014)
  • S. Lesage

    EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?

    Neurobiol. Aging

    (2012)
  • K. Nuytemans

    Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease

    Neurology

    (2013)
  • C. Vilarino-Guell

    DNAJC13 mutations in Parkinson disease

    Hum. Mol. Genet.

    (2013)
  • S. Edvardson

    A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism

    PLoS ONE

    (2012)
  • O. Korvatska

    Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS)

    Hum. Mol. Genet.

    (2013)
  • C.E. Krebs

    The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive parkinsonism with generalized seizures

    Hum. Mutat.

    (2013)
  • M. Quadri

    Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset parkinsonism

    Hum. Mutat.

    (2013)
  • Mutations in COQ2 in familial and sporadic multiple-system atrophy

    N. Engl. J. Med.

    (2013)
  • M.N. Seaman

    The retromer complex – endosomal protein recycling and beyond

    J. Cell Sci.

    (2012)
  • E. Zavodszky

    Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy

    Nat. Commun.

    (2014)
  • J. Follett

    The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer

    Traffic

    (2014)
  • E. Tsika

    Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration

    Hum. Mol. Genet.

    (2014)
  • C.L. Freeman

    RME-8 coordinates the WASH complex with the retromer SNX–BAR dimer to control endosomal tubulation

    J. Cell Sci.

    (2014)
  • A. Hierro

    Functional architecture of the retromer cargo-recognition complex

    Nature

    (2007)
  • A. Rothnie

    A sequential mechanism for clathrin cage disassembly by 70-kDa heat-shock cognate protein (Hsc70) and auxilin

    Proc. Natl. Acad. Sci. U.S.A.

    (2011)
  • G. Nguyen

    Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin

    J. Clin. Invest.

    (2002)
  • F. Riediger

    Prorenin receptor is essential for podocyte autophagy and survival

    J. Am. Soc. Nephrol.

    (2011)
  • C.M. Cruciat

    Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling

    Science

    (2010)
  • S. Olgiati

    PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family

    Neurogenetics

    (2014)
  • S. Winkler

    α-Synuclein and Parkinson disease susceptibility

    Neurology

    (2007)
  • D.M. Maraganore

    Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease

    JAMA

    (2006)
  • Cited by (186)

    • Micronutrient levels in Parkinson's disease

      2023, Vitamins and Minerals in Neurological Disorders
    • Methylation of alpha-synuclein in a Sudanese cohort

      2022, Parkinsonism and Related Disorders
    View all citing articles on Scopus
    View full text