Initial studies focused on early-onset and familial Parkinson’s disease (PD) discovered rare mutations in 16 loci (PARK1-20). Recent, genome-wide association studies (GWAS) have found 26 PD risk loci with small effect size. However, most of the “GWAS hits” contain multiple genes that are equally likely to be affected by associated polymorphisms. Therefore, the currently identified genetic factors explain only 6-7% of the phenotypic variability associated with PD. The most significant GWA signals account for only 3-5% of PD genetic variability. Thus, a significant portion of the genetic contribution in PD remains to be discovered.

PD is a clinically, pathologically and genetically heterogeneous disorder. Recently, genetic studies in complex diseases have provided evidence that clinical phenotypes (categorical classification) can be addressed as a collection of multiple phenotypes. Focusing on specific traits (e.g. biomarkers) of the disease has facilitated its correlation with a genetic signature. Thus, analyzing groups of patients that share heritable clinical features improves ability to identify underlying genetic architecture and uncover novel genes or pathways involved in PD.

Publications

  1. Fernández MV, Kim JH, Budde JP, Black K, Medvedeva A, Saef B, Deming Y, Del-Aguila J, Ibañez L, Dube U, Harari O, Norton J, Chasse R, Morris JC, Goate A; NIA-LOAD family study group; NCRAD, Cruchaga C. Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease. PLoS Genet. 2017;13(11):e1007045. doi: 0.1371/journal.pgen.1007045. PMCID: PMC5683650
  2. Ibanez L, Dube U, Davis AA, Fernandez MV, Budde J, Cooper B, Diez-Fairen M, Ortega-Cubero S, Pastor P, Perlmutter JS, Cruchaga C, Benitez BA. Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease. Front Neuroscience 2018; 12:230. doi: 10.3389/fnins.2018.00230   PMCID: PMC59027
  3. Diez-Fairen M, Benitez BA, Ortega-Cubero S, Lorenzo-Betancor O, Cruchaga C, Lorenzo E, Samaranch L, Carcel M, Obeso JA, Rodriguez-Oroz MC, Aguilar M, Coria F, Pastor MA, Pastor P.  Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population. Neurobiol Aging. 2018; 70:325.
  4. Ibanez L, Dube U, Saef B, Budde J, Black K, Medvedeva A, Del-Aguila JL, Davis AA, Perlmutter JS, Harari O, Benitez BA, Cruchaga C. (2017 November). Parkinson disease polygenic risk score is associated with Parkinson disease satus and age at onset but not with alpha-synuclein cerebrospinal fluid levels. BMC Neurol. 2017 Neurol 17(1):198. PMID:29141588; PMCID:PMC5688622
  5. Ibanez L, Dube U, Budde J, Black K, Medvedeva A, Davis AA, Perlmutter JS, Benitez BA, Cruchaga C.  TMEM230 in Parkinson’s disease. Neurobiol Aging. 2017; 56:212.  PMCID: PMC5526081
  6. Benitez BA, Davis AA, Jin SC, Ibanez L, Ortega-Cubero S, Pastor P, Choi J, Cooper B, Perlmutter JS, Cruchaga C.  Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parksinson’s Disease. Mol Neurodegeneration  2016; 11:29.  PMCID: PMC4837564
  7. Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression.  Neurobiol Aging 2016; 37:209.  PMCID: PMC4688052
  8. Harms M, Neumann, Benitez B, Cooper B, Cooper P, Carrell D, Racette BA, Perlmutter JS, Goate AM and Cruchaga C. Parkinson Disease is not associated with C9ORF72 repeat expansions.. Neurobiol Aging. 2013; 34(5):1519.  PMCID: PMC3566343