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 language | English (US) |
|---|---|
| Pages (from-to) | 152-164 |
| Number of pages | 13 |
| Journal | Journal of Neurology, Neurosurgery and Psychiatry |
| Volume | 88 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2017 |
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ASJC Scopus subject areas
- Surgery
- Clinical Neurology
- Psychiatry and Mental health
Cite this
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 journal › Article
}
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 - Rademakers, Rosa V
AU - Dickson, Dennis W
AU - Graff Radford, Neill R
AU - Petersen, Ronald Carl
AU - Knopman, David S
AU - Josephs, Keith Anthony
AU - Boeve, Bradley F
AU - Parisi, Joseph E
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.
UR - http://www.scopus.com/inward/record.url?scp=85006056898&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006056898&partnerID=8YFLogxK
U2 - 10.1136/jnnp-2016-314411
DO - 10.1136/jnnp-2016-314411
M3 - Article
C2 - 27899424
AN - SCOPUS:85006056898
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 -