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

The IFGC and IPDGC members

Research output: Contribution to journalArticle

26 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.

Original languageEnglish (US)
Pages (from-to)152-164
Number of pages13
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume88
Issue number2
DOIs
StatePublished - Feb 1 2017

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

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

@article{7b3bfebf1b9f450385160d6a2cdf8c86,
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.",
author = "{The IFGC and IPDGC members} and Raffaele Ferrari and Yunpeng Wang and Jana Vandrovcova and Sebastian Guelfi and Aree Witeolar and Karch, {Celeste M.} and Schork, {Andrew J.} and Fan, {Chun C.} and Brewer, {James B.} and Parastoo Momeni and Schellenberg, {Gerard D.} and Dillon, {William P.} and Sugrue, {Leo P.} and Hess, {Christopher P.} and Yokoyama, {Jennifer S.} and Bonham, {Luke W.} and Rabinovici, {Gil D.} and Miller, {Bruce L.} and Andreassen, {Ole A.} and Dale, {Anders M.} and John Hardy and Desikan, {Rahul S.} and R. Ferrari and Hernandez, {D. G.} and Nalls, {M. A.} and Rohrer, {J. D.} and A. Ramasamy and Kwok, {J. B.J.} and C. Dobson-Stone and Schofield, {P. R.} and Halliday, {G. M.} and Hodges, {J. R.} 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 Cairns, {N. J.} and L. Benussi and G. Binetti and R. Ghidoni and G. Forloni and D. Albani and D. Galimberti and Grafman, {Jordan Henry}",
year = "2017",
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language = "English (US)",
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pages = "152--164",
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Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. / The IFGC and IPDGC members.

In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 88, No. 2, 01.02.2017, p. 152-164.

Research output: Contribution to journalArticle

TY - JOUR

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

AU - The IFGC and IPDGC members

AU - Ferrari, Raffaele

AU - Wang, Yunpeng

AU - Vandrovcova, Jana

AU - Guelfi, Sebastian

AU - Witeolar, Aree

AU - Karch, Celeste M.

AU - Schork, Andrew J.

AU - Fan, Chun C.

AU - Brewer, James B.

AU - Momeni, Parastoo

AU - Schellenberg, Gerard D.

AU - Dillon, William P.

AU - Sugrue, Leo P.

AU - Hess, Christopher P.

AU - Yokoyama, Jennifer S.

AU - Bonham, Luke W.

AU - Rabinovici, Gil D.

AU - Miller, Bruce L.

AU - Andreassen, Ole A.

AU - Dale, Anders M.

AU - Hardy, John

AU - Desikan, Rahul S.

AU - Ferrari, R.

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 - Grafman, Jordan Henry

PY - 2017/2/1

Y1 - 2017/2/1

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.

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.

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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 -