Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

R. Ferrari, Y. Wang, J. Vandrovcova, S. Guelfi, A. Witeolar, C.M. Karch, A.J. Schork, C.C. Fan, J.B. Brewer, P. Momeni, G.D. Schellenberg, W.P. Dillon, L.P. Sugrue, C.P. Hess, J.S. Yokoyama, L.W. Bonham, G.D. Rabinovici, B.L. Miller, O.A. Andreassen, A.M. DaleJ. Hardy, R.S. Desikan, D.G. Hernandez, M.A. Nalls, J.D. Rohrer, A. Ramasamy, J.B.J. Kwok, C. Dobson-Stone, P.R. Schofield, G.M. Halliday, J.R. Hodges, O. Piguet, L. Bartley, E. Thompson, E. Haan, I. Hernández, A. Ruiz, M. Boada, B. Borroni, A. Padovani, C. Cruchaga, N.J. Cairns, L. Benussi, G. Binetti, R. Ghidoni, G. Forloni, D. Albani, D. Galimberti, C. Fenoglio, M. Serpente, E. Scarpini, J. Clarimón, A. Lleó, R. Blesa, M. Landqvist Waldö, K. Nilsson, C. Nilsson, I.R.A. Mackenzie, G-Y.R. Hsiung, D.M.A. Mann, J. Grafman, C.M. Morris, J. Attems, T.D. Griffiths, I.G. McKeith, A.J. Thomas, P. Pietrini, E.D. Huey, E.M. Wassermann, A. Baborie, E. Jaros, M.C. Tierney, P. Pastor, C. Razquin, S. Ortega-Cubero, E. Alonso, R. Perneczky, J. Diehl-Schmid, P. Alexopoulos, A. Kurz, I. Rainero, E. Rubino, L. Pinessi, E. Rogaeva, P. St George-Hyslop, G. Rossi, F. Tagliavini, G. Giaccone, J.B. Rowe, J.C.M. Schlachetzki, J. Uphill, J. Collinge, S. Mead, A. Danek, V.M. Van Deerlin, M. Grossman, J.Q. Trojanowski, J. van der Zee, M. Cruts, C. Van Broeckhoven, S.F. Cappa, I. Leber, D. Hannequin, V. Golfier, M. Vercelletto, A. Brice, B. Nacmias, S. Sorbi, S. Bagnoli, I. Piaceri, J.E. Nielsen, L.E. Hjermind, M. Riemenschneider, M. Mayhaus, B. Ibach, G. Gasparoni, S. Pichler, W. Gu, M.N. Rossor, N.C. Fox, J.D. Warren, M.G. Spillantini, H.R. Morris, P. Rizzu, P. Heutink, J.S. Snowden, S. Rollinson, A. Richardson, A. Gerhard, A.C. Bruni, R. Maletta, F. Frangipane, C. Cupidi, L. Bernardi, M. Anfossi, M. Gallo, M.E. Conidi, N. Smirne, R. Rademakers, M. Baker, D.W. Dickson, N.R. Graff-Radford, R.C. Petersen, D. Knopman, K.A. Josephs, B.F. Boeve, J.E. Parisi, W.W. Seeley, A.M. Karydas, H. Rosen, J.C. van Swieten, E.G.P. Dopper, H. Seelaar, Y.A.L. Pijnenburg, P. Scheltens, G. Logroscino, R. Capozzo, V. Novelli, A.A. Puca, M. Franceschi, A. Postiglione, G. Milan, P. Sorrentino, M. Kristiansen, H-H. Chiang, C. Graff, F. Pasquier, A. Rollin, V. Deramecourt, T. Lebouvier, D. Kapogiannis, L. Ferrucci, S. Pickering-Brown, A.B. Singleton

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10 -12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10 -7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk. © Published by the BMJ Publishing Group Limited.
Original languageEnglish
Pages (from-to)152-164
Number of pages13
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume88
Issue number2
DOIs
Publication statusPublished - 2017

Fingerprint

Frontotemporal Dementia
Parkinson Disease
Alzheimer Disease
Genetic Pleiotropy
Single Nucleotide Polymorphism
Genomics
3' Untranslated Regions
Neurodegenerative Diseases
Haplotypes
Meta-Analysis
Alleles
Genome

Keywords

  • apolipoprotein E
  • HLA antigen
  • tau protein
  • 3' untranslated region
  • allele
  • Alzheimer disease
  • APOE gene
  • Article
  • chromosome 12
  • chromosome 13
  • chromosome 4
  • controlled study
  • frontotemporal dementia
  • gene expression
  • gene linkage disequilibrium
  • gene location
  • gene locus
  • genetic association
  • genetic variability
  • genome-wide association study
  • haplotype
  • HLA gene
  • human
  • major clinical study
  • MAPT gene
  • overlapping gene
  • Parkinson disease
  • pathology
  • phenotype
  • pleiotropy
  • risk factor
  • single nucleotide polymorphism
  • genetic predisposition
  • genetics
  • genotype
  • Alleles
  • Alzheimer Disease
  • Frontotemporal Dementia
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Parkinson Disease
  • Polymorphism, Single Nucleotide

Cite this

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. / Ferrari, R.; Wang, Y.; Vandrovcova, J.; Guelfi, S.; Witeolar, A.; Karch, C.M.; Schork, A.J.; Fan, C.C.; Brewer, J.B.; Momeni, P.; Schellenberg, G.D.; Dillon, W.P.; Sugrue, L.P.; Hess, C.P.; Yokoyama, J.S.; Bonham, L.W.; Rabinovici, G.D.; Miller, B.L.; Andreassen, O.A.; Dale, A.M.; Hardy, J.; Desikan, R.S.; Hernandez, D.G.; Nalls, M.A.; Rohrer, J.D.; Ramasamy, A.; Kwok, J.B.J.; Dobson-Stone, C.; Schofield, P.R.; Halliday, G.M.; Hodges, J.R.; Piguet, O.; Bartley, L.; Thompson, E.; Haan, E.; Hernández, I.; Ruiz, A.; Boada, M.; Borroni, B.; Padovani, A.; Cruchaga, C.; Cairns, N.J.; Benussi, L.; Binetti, G.; Ghidoni, R.; Forloni, G.; Albani, D.; Galimberti, D.; Fenoglio, C.; Serpente, M.; Scarpini, E.; Clarimón, J.; Lleó, A.; Blesa, R.; Landqvist Waldö, M.; Nilsson, K.; Nilsson, C.; Mackenzie, I.R.A.; Hsiung, G-Y.R.; Mann, D.M.A.; Grafman, J.; Morris, C.M.; Attems, J.; Griffiths, T.D.; McKeith, I.G.; Thomas, A.J.; Pietrini, P.; Huey, E.D.; Wassermann, E.M.; Baborie, A.; Jaros, E.; Tierney, M.C.; Pastor, P.; Razquin, C.; Ortega-Cubero, S.; Alonso, E.; Perneczky, R.; Diehl-Schmid, J.; Alexopoulos, P.; Kurz, A.; Rainero, I.; Rubino, E.; Pinessi, L.; Rogaeva, E.; St George-Hyslop, P.; Rossi, G.; Tagliavini, F.; Giaccone, G.; Rowe, J.B.; Schlachetzki, J.C.M.; Uphill, J.; Collinge, J.; Mead, S.; Danek, A.; Van Deerlin, V.M.; Grossman, M.; Trojanowski, J.Q.; van der Zee, J.; Cruts, M.; Van Broeckhoven, C.; Cappa, S.F.; Leber, I.; Hannequin, D.; Golfier, V.; Vercelletto, M.; Brice, A.; Nacmias, B.; Sorbi, S.; Bagnoli, S.; Piaceri, I.; Nielsen, J.E.; Hjermind, L.E.; Riemenschneider, M.; Mayhaus, M.; Ibach, B.; Gasparoni, G.; Pichler, S.; Gu, W.; Rossor, M.N.; Fox, N.C.; Warren, J.D.; Spillantini, M.G.; Morris, H.R.; Rizzu, P.; Heutink, P.; Snowden, J.S.; Rollinson, S.; Richardson, A.; Gerhard, A.; Bruni, A.C.; Maletta, R.; Frangipane, F.; Cupidi, C.; Bernardi, L.; Anfossi, M.; Gallo, M.; Conidi, M.E.; Smirne, N.; Rademakers, R.; Baker, M.; Dickson, D.W.; Graff-Radford, N.R.; Petersen, R.C.; Knopman, D.; Josephs, K.A.; Boeve, B.F.; Parisi, J.E.; Seeley, W.W.; Karydas, A.M.; Rosen, H.; van Swieten, J.C.; Dopper, E.G.P.; Seelaar, H.; Pijnenburg, Y.A.L.; Scheltens, P.; Logroscino, G.; Capozzo, R.; Novelli, V.; Puca, A.A.; Franceschi, M.; Postiglione, A.; Milan, G.; Sorrentino, P.; Kristiansen, M.; Chiang, H-H.; Graff, C.; Pasquier, F.; Rollin, A.; Deramecourt, V.; Lebouvier, T.; Kapogiannis, D.; Ferrucci, L.; Pickering-Brown, S.; Singleton, A.B.

In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 88, No. 2, 2017, p. 152-164.

Research output: Contribution to journalArticle

Ferrari, R, Wang, Y, Vandrovcova, J, Guelfi, S, Witeolar, A, Karch, CM, Schork, AJ, Fan, CC, Brewer, JB, Momeni, P, Schellenberg, GD, Dillon, WP, Sugrue, LP, Hess, CP, Yokoyama, JS, Bonham, LW, Rabinovici, GD, Miller, BL, Andreassen, OA, Dale, AM, Hardy, J, Desikan, RS, Hernandez, DG, Nalls, MA, Rohrer, JD, Ramasamy, A, Kwok, JBJ, Dobson-Stone, C, Schofield, PR, Halliday, GM, Hodges, JR, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, NJ, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, IRA, Hsiung, G-YR, Mann, DMA, Grafman, J, Morris, CM, Attems, J, Griffiths, TD, McKeith, IG, Thomas, AJ, Pietrini, P, Huey, ED, Wassermann, EM, Baborie, A, Jaros, E, Tierney, MC, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, JB, Schlachetzki, JCM, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, VM, Grossman, M, Trojanowski, JQ, van der Zee, J, Cruts, M, Van Broeckhoven, C, Cappa, SF, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, JE, Hjermind, LE, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, MN, Fox, NC, Warren, JD, Spillantini, MG, Morris, HR, Rizzu, P, Heutink, P, Snowden, JS, Rollinson, S, Richardson, A, Gerhard, A, Bruni, AC, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, ME, Smirne, N, Rademakers, R, Baker, M, Dickson, DW, Graff-Radford, NR, Petersen, RC, Knopman, D, Josephs, KA, Boeve, BF, Parisi, JE, Seeley, WW, Karydas, AM, Rosen, H, van Swieten, JC, Dopper, EGP, Seelaar, H, Pijnenburg, YAL, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, AA, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S & Singleton, AB 2017, 'Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases', Journal of Neurology, Neurosurgery and Psychiatry, vol. 88, no. 2, pp. 152-164. https://doi.org/10.1136/jnnp-2016-314411
Ferrari, R. ; Wang, Y. ; Vandrovcova, J. ; Guelfi, S. ; Witeolar, A. ; Karch, C.M. ; Schork, A.J. ; Fan, C.C. ; Brewer, J.B. ; Momeni, P. ; Schellenberg, G.D. ; Dillon, W.P. ; Sugrue, L.P. ; Hess, C.P. ; Yokoyama, J.S. ; Bonham, L.W. ; Rabinovici, G.D. ; Miller, B.L. ; Andreassen, O.A. ; Dale, A.M. ; Hardy, J. ; Desikan, R.S. ; Hernandez, D.G. ; Nalls, M.A. ; Rohrer, J.D. ; Ramasamy, A. ; Kwok, J.B.J. ; Dobson-Stone, C. ; Schofield, P.R. ; Halliday, G.M. ; Hodges, J.R. ; Piguet, O. ; Bartley, L. ; Thompson, E. ; Haan, E. ; Hernández, I. ; Ruiz, A. ; Boada, M. ; Borroni, B. ; Padovani, A. ; Cruchaga, C. ; Cairns, N.J. ; Benussi, L. ; Binetti, G. ; Ghidoni, R. ; Forloni, G. ; Albani, D. ; Galimberti, D. ; Fenoglio, C. ; Serpente, M. ; Scarpini, E. ; Clarimón, J. ; Lleó, A. ; Blesa, R. ; Landqvist Waldö, M. ; Nilsson, K. ; Nilsson, C. ; Mackenzie, I.R.A. ; Hsiung, G-Y.R. ; Mann, D.M.A. ; Grafman, J. ; Morris, C.M. ; Attems, J. ; Griffiths, T.D. ; McKeith, I.G. ; Thomas, A.J. ; Pietrini, P. ; Huey, E.D. ; Wassermann, E.M. ; Baborie, A. ; Jaros, E. ; Tierney, M.C. ; Pastor, P. ; Razquin, C. ; Ortega-Cubero, S. ; Alonso, E. ; Perneczky, R. ; Diehl-Schmid, J. ; Alexopoulos, P. ; Kurz, A. ; Rainero, I. ; Rubino, E. ; Pinessi, L. ; Rogaeva, E. ; St George-Hyslop, P. ; Rossi, G. ; Tagliavini, F. ; Giaccone, G. ; Rowe, J.B. ; Schlachetzki, J.C.M. ; Uphill, J. ; Collinge, J. ; Mead, S. ; Danek, A. ; Van Deerlin, V.M. ; Grossman, M. ; Trojanowski, J.Q. ; van der Zee, J. ; Cruts, M. ; Van Broeckhoven, C. ; Cappa, S.F. ; Leber, I. ; Hannequin, D. ; Golfier, V. ; Vercelletto, M. ; Brice, A. ; Nacmias, B. ; Sorbi, S. ; Bagnoli, S. ; Piaceri, I. ; Nielsen, J.E. ; Hjermind, L.E. ; Riemenschneider, M. ; Mayhaus, M. ; Ibach, B. ; Gasparoni, G. ; Pichler, S. ; Gu, W. ; Rossor, M.N. ; Fox, N.C. ; Warren, J.D. ; Spillantini, M.G. ; Morris, H.R. ; Rizzu, P. ; Heutink, P. ; Snowden, J.S. ; Rollinson, S. ; Richardson, A. ; Gerhard, A. ; Bruni, A.C. ; Maletta, R. ; Frangipane, F. ; Cupidi, C. ; Bernardi, L. ; Anfossi, M. ; Gallo, M. ; Conidi, M.E. ; Smirne, N. ; Rademakers, R. ; Baker, M. ; Dickson, D.W. ; Graff-Radford, N.R. ; Petersen, R.C. ; Knopman, D. ; Josephs, K.A. ; Boeve, B.F. ; Parisi, J.E. ; Seeley, W.W. ; Karydas, A.M. ; Rosen, H. ; van Swieten, J.C. ; Dopper, E.G.P. ; Seelaar, H. ; Pijnenburg, Y.A.L. ; Scheltens, P. ; Logroscino, G. ; Capozzo, R. ; Novelli, V. ; Puca, A.A. ; Franceschi, M. ; Postiglione, A. ; Milan, G. ; Sorrentino, P. ; Kristiansen, M. ; Chiang, H-H. ; Graff, C. ; Pasquier, F. ; Rollin, A. ; Deramecourt, V. ; Lebouvier, T. ; Kapogiannis, D. ; Ferrucci, L. ; Pickering-Brown, S. ; Singleton, A.B. / Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. In: Journal of Neurology, Neurosurgery and Psychiatry. 2017 ; Vol. 88, No. 2. pp. 152-164.
@article{31024c1d0af5411fa152e61be5bd8f6c,
title = "Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases",
abstract = "Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10 -12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10 -7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk. {\circledC} Published by the BMJ Publishing Group Limited.",
keywords = "apolipoprotein E, HLA antigen, tau protein, 3' untranslated region, allele, Alzheimer disease, APOE gene, Article, chromosome 12, chromosome 13, chromosome 4, controlled study, frontotemporal dementia, gene expression, gene linkage disequilibrium, gene location, gene locus, genetic association, genetic variability, genome-wide association study, haplotype, HLA gene, human, major clinical study, MAPT gene, overlapping gene, Parkinson disease, pathology, phenotype, pleiotropy, risk factor, single nucleotide polymorphism, genetic predisposition, genetics, genotype, Alleles, Alzheimer Disease, Frontotemporal Dementia, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Parkinson Disease, Polymorphism, Single Nucleotide",
author = "R. Ferrari and Y. Wang and J. Vandrovcova and S. Guelfi and A. Witeolar and C.M. Karch and A.J. Schork and C.C. Fan and J.B. Brewer and P. Momeni and G.D. Schellenberg and W.P. Dillon and L.P. Sugrue and C.P. Hess and J.S. Yokoyama and L.W. Bonham and G.D. Rabinovici and B.L. Miller and O.A. Andreassen and A.M. Dale and J. Hardy and R.S. Desikan and D.G. Hernandez and M.A. Nalls and J.D. Rohrer and A. Ramasamy and J.B.J. Kwok and C. Dobson-Stone and P.R. Schofield and G.M. Halliday and J.R. Hodges and O. Piguet and L. Bartley and E. Thompson and E. Haan and I. Hern{\'a}ndez and A. Ruiz and M. Boada and B. Borroni and A. Padovani and C. Cruchaga and N.J. Cairns and L. Benussi and G. Binetti and R. Ghidoni and G. Forloni and D. Albani and D. Galimberti and C. Fenoglio and M. Serpente and E. Scarpini and J. Clarim{\'o}n and A. Lle{\'o} and R. Blesa and {Landqvist Wald{\"o}}, M. and K. Nilsson and C. Nilsson and I.R.A. Mackenzie and G-Y.R. Hsiung and D.M.A. Mann and J. Grafman and C.M. Morris and J. Attems and T.D. Griffiths and I.G. McKeith and A.J. Thomas and P. Pietrini and E.D. Huey and E.M. Wassermann and A. Baborie and E. Jaros and M.C. Tierney and P. Pastor and C. Razquin and S. Ortega-Cubero and E. Alonso and R. Perneczky and J. Diehl-Schmid and P. Alexopoulos and A. Kurz and I. Rainero and E. Rubino and L. Pinessi and E. Rogaeva and {St George-Hyslop}, P. and G. Rossi and F. Tagliavini and G. Giaccone and J.B. Rowe and J.C.M. Schlachetzki and J. Uphill and J. Collinge and S. Mead and A. Danek and {Van Deerlin}, V.M. and M. Grossman and J.Q. Trojanowski and {van der Zee}, J. and M. Cruts and {Van Broeckhoven}, C. and S.F. Cappa and I. Leber and D. Hannequin and V. Golfier and M. Vercelletto and A. Brice and B. Nacmias and S. Sorbi and S. Bagnoli and I. Piaceri and J.E. Nielsen and L.E. Hjermind and M. Riemenschneider and M. Mayhaus and B. Ibach and G. Gasparoni and S. Pichler and W. Gu and M.N. Rossor and N.C. Fox and J.D. Warren and M.G. Spillantini and H.R. Morris and P. Rizzu and P. Heutink and J.S. Snowden and S. Rollinson and A. Richardson and A. Gerhard and A.C. Bruni and R. Maletta and F. Frangipane and C. Cupidi and L. Bernardi and M. Anfossi and M. Gallo and M.E. Conidi and N. Smirne and R. Rademakers and M. Baker and D.W. Dickson and N.R. Graff-Radford and R.C. Petersen and D. Knopman and K.A. Josephs and B.F. Boeve and J.E. Parisi and W.W. Seeley and A.M. Karydas and H. Rosen and {van Swieten}, J.C. and E.G.P. Dopper and H. Seelaar and Y.A.L. Pijnenburg and P. Scheltens and G. Logroscino and R. Capozzo and V. Novelli and A.A. Puca and M. Franceschi and A. Postiglione and G. Milan and P. Sorrentino and M. Kristiansen and H-H. Chiang and C. Graff and F. Pasquier and A. Rollin and V. Deramecourt and T. Lebouvier and D. Kapogiannis and L. Ferrucci and S. Pickering-Brown and A.B. Singleton",
note = "Cited By :5 Export Date: 26 February 2018 CODEN: JNNPA Correspondence Address: Ferrari, R.; Department of Molecular Neuroscience, University College London, Russell Square House, United Kingdom; email: r.ferrari@ucl.ac.uk",
year = "2017",
doi = "10.1136/jnnp-2016-314411",
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pages = "152--164",
journal = "Journal of Neurology, Neurosurgery and Psychiatry",
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TY - JOUR

T1 - Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

AU - Ferrari, R.

AU - Wang, Y.

AU - Vandrovcova, J.

AU - Guelfi, S.

AU - Witeolar, A.

AU - Karch, C.M.

AU - Schork, A.J.

AU - Fan, C.C.

AU - Brewer, J.B.

AU - Momeni, P.

AU - Schellenberg, G.D.

AU - Dillon, W.P.

AU - Sugrue, L.P.

AU - Hess, C.P.

AU - Yokoyama, J.S.

AU - Bonham, L.W.

AU - Rabinovici, G.D.

AU - Miller, B.L.

AU - Andreassen, O.A.

AU - Dale, A.M.

AU - Hardy, J.

AU - Desikan, R.S.

AU - Hernandez, D.G.

AU - Nalls, M.A.

AU - Rohrer, J.D.

AU - Ramasamy, A.

AU - Kwok, J.B.J.

AU - Dobson-Stone, C.

AU - Schofield, P.R.

AU - Halliday, G.M.

AU - Hodges, J.R.

AU - Piguet, O.

AU - Bartley, L.

AU - Thompson, E.

AU - Haan, E.

AU - Hernández, I.

AU - Ruiz, A.

AU - Boada, M.

AU - Borroni, B.

AU - Padovani, A.

AU - Cruchaga, C.

AU - Cairns, N.J.

AU - Benussi, L.

AU - Binetti, G.

AU - Ghidoni, R.

AU - Forloni, G.

AU - Albani, D.

AU - Galimberti, D.

AU - Fenoglio, C.

AU - Serpente, M.

AU - Scarpini, E.

AU - Clarimón, J.

AU - Lleó, A.

AU - Blesa, R.

AU - Landqvist Waldö, M.

AU - Nilsson, K.

AU - Nilsson, C.

AU - Mackenzie, I.R.A.

AU - Hsiung, G-Y.R.

AU - Mann, D.M.A.

AU - Grafman, J.

AU - Morris, C.M.

AU - Attems, J.

AU - Griffiths, T.D.

AU - McKeith, I.G.

AU - Thomas, A.J.

AU - Pietrini, P.

AU - Huey, E.D.

AU - Wassermann, E.M.

AU - Baborie, A.

AU - Jaros, E.

AU - Tierney, M.C.

AU - Pastor, P.

AU - Razquin, C.

AU - Ortega-Cubero, S.

AU - Alonso, E.

AU - Perneczky, R.

AU - Diehl-Schmid, J.

AU - Alexopoulos, P.

AU - Kurz, A.

AU - Rainero, I.

AU - Rubino, E.

AU - Pinessi, L.

AU - Rogaeva, E.

AU - St George-Hyslop, P.

AU - Rossi, G.

AU - Tagliavini, F.

AU - Giaccone, G.

AU - Rowe, J.B.

AU - Schlachetzki, J.C.M.

AU - Uphill, J.

AU - Collinge, J.

AU - Mead, S.

AU - Danek, A.

AU - Van Deerlin, V.M.

AU - Grossman, M.

AU - Trojanowski, J.Q.

AU - van der Zee, J.

AU - Cruts, M.

AU - Van Broeckhoven, C.

AU - Cappa, S.F.

AU - Leber, I.

AU - Hannequin, D.

AU - Golfier, V.

AU - Vercelletto, M.

AU - Brice, A.

AU - Nacmias, B.

AU - Sorbi, S.

AU - Bagnoli, S.

AU - Piaceri, I.

AU - Nielsen, J.E.

AU - Hjermind, L.E.

AU - Riemenschneider, M.

AU - Mayhaus, M.

AU - Ibach, B.

AU - Gasparoni, G.

AU - Pichler, S.

AU - Gu, W.

AU - Rossor, M.N.

AU - Fox, N.C.

AU - Warren, J.D.

AU - Spillantini, M.G.

AU - Morris, H.R.

AU - Rizzu, P.

AU - Heutink, P.

AU - Snowden, J.S.

AU - Rollinson, S.

AU - Richardson, A.

AU - Gerhard, A.

AU - Bruni, A.C.

AU - Maletta, R.

AU - Frangipane, F.

AU - Cupidi, C.

AU - Bernardi, L.

AU - Anfossi, M.

AU - Gallo, M.

AU - Conidi, M.E.

AU - Smirne, N.

AU - Rademakers, R.

AU - Baker, M.

AU - Dickson, D.W.

AU - Graff-Radford, N.R.

AU - Petersen, R.C.

AU - Knopman, D.

AU - Josephs, K.A.

AU - Boeve, B.F.

AU - Parisi, J.E.

AU - Seeley, W.W.

AU - Karydas, A.M.

AU - Rosen, H.

AU - van Swieten, J.C.

AU - Dopper, E.G.P.

AU - Seelaar, H.

AU - Pijnenburg, Y.A.L.

AU - Scheltens, P.

AU - Logroscino, G.

AU - Capozzo, R.

AU - Novelli, V.

AU - Puca, A.A.

AU - Franceschi, M.

AU - Postiglione, A.

AU - Milan, G.

AU - Sorrentino, P.

AU - Kristiansen, M.

AU - Chiang, H-H.

AU - Graff, C.

AU - Pasquier, F.

AU - Rollin, A.

AU - Deramecourt, V.

AU - Lebouvier, T.

AU - Kapogiannis, D.

AU - Ferrucci, L.

AU - Pickering-Brown, S.

AU - Singleton, A.B.

N1 - Cited By :5 Export Date: 26 February 2018 CODEN: JNNPA Correspondence Address: Ferrari, R.; Department of Molecular Neuroscience, University College London, Russell Square House, United Kingdom; email: r.ferrari@ucl.ac.uk

PY - 2017

Y1 - 2017

N2 - Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10 -12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10 -7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk. © Published by the BMJ Publishing Group Limited.

AB - Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10 -12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10 -7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk. © Published by the BMJ Publishing Group Limited.

KW - apolipoprotein E

KW - HLA antigen

KW - tau protein

KW - 3' untranslated region

KW - allele

KW - Alzheimer disease

KW - APOE gene

KW - Article

KW - chromosome 12

KW - chromosome 13

KW - chromosome 4

KW - controlled study

KW - frontotemporal dementia

KW - gene expression

KW - gene linkage disequilibrium

KW - gene location

KW - gene locus

KW - genetic association

KW - genetic variability

KW - genome-wide association study

KW - haplotype

KW - HLA gene

KW - human

KW - major clinical study

KW - MAPT gene

KW - overlapping gene

KW - Parkinson disease

KW - pathology

KW - phenotype

KW - pleiotropy

KW - risk factor

KW - single nucleotide polymorphism

KW - genetic predisposition

KW - genetics

KW - genotype

KW - Alleles

KW - Alzheimer Disease

KW - Frontotemporal Dementia

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Parkinson Disease

KW - Polymorphism, Single Nucleotide

U2 - 10.1136/jnnp-2016-314411

DO - 10.1136/jnnp-2016-314411

M3 - Article

VL - 88

SP - 152

EP - 164

JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

SN - 0022-3050

IS - 2

ER -