Genetic Overlap across Neurodegeneration

Aging populations worldwide, and particularly developed countries, face an increasing burden of neurodegenerative diseases.  Cognitive impairment is the most prominent in Alzheimer’s disease (AD) and in Frontotemporal dementia (FTD), but it is also an important feature of Parkinson’s disease (PD) (dementia is present in 80% of patients in studies of long-term follow up).

Although genome-wide meta-analysis failed to identify variants associated with both PD and AD, studies that tested the association of variants identified in one specific disease in another neurodegenerative disease revealed positive results. For example, ours and other groups have identified that the non-synonymous variant in TREM2 R47H initially associated for developing risk for AD also increases risk of  PD and FTD-like syndrome.  Similarly, there is increasing evidence that common pathways are involved in pathogenesis of  FTD, AD and PD. FTD genome-wide studies identified signals encompassing HLA locus, related to the immune system and RAB38/CTSC genes related protein trafficking to lysosomal-related organelles and activation of serine proteinases in cells involved in immune process.  Variants in genes involved in the immune system, including CLU, CR1, ABCA7, CD33, and EPHA1; as well as in genes related to endosome–lysosome pathways (BIN1, PICALM, CD2AP, EPHA1, SORL1, RIN3, MEF2C, and MADD) were identified in GWAS of AD. And genetic factors, such as LRRK2, GBA, SNCA, PARK2, PINK1, PARK7 and SCARB2, are involved in the autophagy-lysosome pathway while LRRK2, PARK7 , GBA, BST1, HLA-DRB5, STK39 genes and loci are associated with immune system in PD.

We hypothesize that genetic variants and pathways are associated with all these neurodegenerative diseases. The goal of this study is to use genome-wide association data, exome chip data and whole genome/exome sequence data from unrelated individuals to identify novel genetic modifiers that accelerate disease or protect against development of AD, PD, FTD and other complex traits.

plots showing enrichment of PSP I, Manhattan plot of variants effecting PSP. Gene network illustration.

Publications

  1. Broce IJ, Tan CH, Fan CC, Jansen I, Savage JE, Witoelar A, Wen N, Hess CP, Dillon WP, Glastonbury CM, Glymour M, Yokoyama JS, Elahi FM, Rabinovici GD, Miller BL, Mormino EC, Sperling RA, Bennett DA, McEvoy LK, Brewer JB, Feldman HH, Hyman BT, Pericak-Vance M, Haines JL, Farrer LA, Mayeux R, Schellenberg GD, Yaffe K, Sugrue LP, Dale AM, Posthuma D, Andreassen OA, Karch CM, Desikan RS. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. Acta Neuropathol. 2019 Feb;137(2):209-226. doi: 10.1007/s00401-018-1928-6. Epub 2018 Nov 9. PMID: 30413934
  2. Bonham LW, Karch CM, Fan CC, Tan C, Geier EG, Wang Y, Wen N, Broce IJ, Li Y, Barkovich MJ, Ferrari R, Hardy J, Momeni P, Höglinger G, Müller U, Hess CP, Sugrue LP, Dillon WP, Schellenberg GD, Miller BL, Andreassen OA, Dale AM, Barkovich AJ, Yokoyama JS, Desikan RS; International FTD-Genomics Consortium (IFGC); International Parkinson’s Disease Genetics Consortium (IPDGC); International Genomics of Alzheimer’s Project (IGAP). CXCR4 involvement in neurodegenerative diseases. Transl Psychiatry. 2018 Apr 11;8(1):73. doi: 10.1038/s41398-017-0049-7. PMID: 2963646
  3. Karch CM, Wen N, Fan CC, Yokoyama JS, Kouri N, Ross OA, Höglinger G, Müller U, Ferrari R, Hardy J, Schellenberg GD, Sleiman PM, Momeni P, Hess CP, Miller BL, Sharma M, Van Deerlin V, Smeland OB, Andreassen OA, Dale AM, Desikan RS; International Frontotemporal Dementia (FTD)–Genomics Consortium, International Collaboration for Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium, and International Parkinson’s Disease Genomics Consortium. Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum. JAMA Neurol. 2018 Jul 1;75(7):860-875. doi: 10.1001/jamaneurol.2018.0372. PMID: 2963071
  4. Jiang S, Wen N, Li Z, Dube U, Del Aguila J, Budde J, Martinez R, Hsu S, Fernandez MV, Cairns NJ; Dominantly Inherited Alzheimer Network (DIAN); International FTD-Genomics Consortium (IFGC), Harari O, Cruchaga C, Karch CM.  Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP.  Transl Psychiatry. 2018; 8(1):265.
  5. Broce I, Karch CM, Wen N, Fan CC, Wang Y, Tan CH, Kouri N, Ross OA, Höglinger GU, Muller U, Hardy J; International FTD-Genomics Consortium, Momeni P, Hess CP, Dillon WP, Miller ZA, Bonham LW, Rabinovici GD, Rosen HJ, Schellenberg GD, Franke A, Karlsen TH, Veldink JH, Ferrari R, Yokoyama JS, Miller BL, Andreassen OA, Dale AM, Desikan RS, Sugrue LP. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Med. 2018 Jan 9;15(1):e1002487. doi: 10.1371/journal.pmed.1002487. eCollection 2018 Jan. Erratum in: PLoS Med. 2018 Jan 29;15(1):e1002504. PMID: 29315334
  6. 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.
  7. Cruchaga C, Del-Aguila JL, Saef B, Black K, Fernandez MV, Budde J, Ibanez L, Kapoor M, Tosto G, Mayeux RP, Holtzman DM, Fagan AM, Morris JC, Bateman RJ, Goate AM; Dominantly Inherited Alzheimer Network (DIAN); Disease Neuroimaging Initiative (ADNI); NIA-LOAD family study, Harari O. Polygenic risk score of sporadic late-onset Alzheimer’s disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 2018; (2):205-214. PMCID:PMC5803427
  8. 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
  9. Yokoyama JS, Karch CM, Fan CC, Bonham LW, Kouri N, Ross OA, Rademakers R, Kim J, Wang Y, Höglinger GU, Müller U, Ferrari R, Hardy J; International FTD-Genomics Consortium (IFGC), Momeni P, Sugrue LP, Hess CP, James Barkovich A, Boxer AL, Seeley WW, Rabinovici GD, Rosen HJ, Miller BL, Schmansky NJ, Fischl B, Hyman BT, Dickson DW, Schellenberg GD, Andreassen OA, Dale AM, Desikan RS. Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathol. 2017 May;133(5):825-837. doi: 10.1007/s00401-017-1693-y. Epub 2017 Mar 7. PMID: 28271184
  10. 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
  11. Deming Y, Cruchaga C. TMEM106B: a strong FTLD disease modifier. Acta Neuropathol 2014; 127(3):419-22.