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Title | Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | 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 |
Corporate Authors | International FTD-Genomics Consortium(IFGC),, International Parkinson's Disease Genomics Consortium(IPDGC),, International Genomics of Alzheimer's Project(IGAP), |
Journal | J Neurol Neurosurg Psychiatry |
Volume | 88 |
Issue | 2 |
Pagination | 152-164 |
Date Published | 2017 02 |
ISSN | 1468-330X |
Keywords | Alleles, Alzheimer Disease, Frontotemporal Dementia, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Parkinson Disease, Polymorphism, Single Nucleotide |
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>75 000 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), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10) 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. |
DOI | 10.1136/jnnp-2016-314411 |
Alternate Journal | J. Neurol. Neurosurg. Psychiatry |
PubMed ID | 27899424 |
PubMed Central ID | PMC5237405 |
Grant List | P30 AG010124 / AG / NIA NIH HHS / United States K01 AG049152 / AG / NIA NIH HHS / United States G1100540 / / Medical Research Council / United Kingdom MC_U123160657 / / Medical Research Council / United Kingdom K24 AG045333 / AG / NIA NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States P01 AG017586 / AG / NIA NIH HHS / United States MC_U123160651 / / Medical Research Council / United Kingdom U01 AG032984 / AG / NIA NIH HHS / United States G1100643 / / Medical Research Council / United Kingdom U24 DA041123 / DA / NIDA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States MC_U105597119 / / Medical Research Council / United Kingdom G0900652 / / Medical Research Council / United Kingdom K-1501 / / Parkinson's UK / United Kingdom K01 AG046374 / AG / NIA NIH HHS / United States G0502157 / / Medical Research Council / United Kingdom G0301152 / / Medical Research Council / United Kingdom G0400074 / / Medical Research Council / United Kingdom MR/J009482/1 / / Medical Research Council / United Kingdom MR/M023664/1 / / Medical Research Council / United Kingdom MR/M501724/1 / / Medical Research Council / United Kingdom MR/M008525/1 / / Medical Research Council / United Kingdom G0700943 / / Medical Research Council / United Kingdom |