Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases
Autor: | Ferrari, Raffaele, Wang, Yunpeng, Vandrovcova, Jana, Guelfi, Sebastian, Witeolar, Aree, Karch, Celeste M, Schork, Andrew J, Fan, Chun C, Brewer, James B, International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genomics Consortium (IPDGC), International Genomics Of Alzheimer's Project (IGAP), Momeni, Parastoo, Schellenberg, Gerard D, Dillon, William P, Sugrue, Leo P, Hess, Christopher P, Yokoyama, Jennifer S, Bonham, Luke W, Rabinovici, Gil D, Miller, Bruce L, Andreassen, Ole A, Dale, Anders M, Hardy, John, Desikan, Rahul S |
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Přispěvatelé: | Ferrari, Raffaele [0000-0002-6208-5260], Apollo - University of Cambridge Repository |
Rok vydání: | 2018 |
Předmět: |
Aging
Genotype Neurodegenerative Alzheimer's Disease Medical and Health Sciences Polymorphism Single Nucleotide Alzheimer Disease mental disorders Acquired Cognitive Impairment Genetics 2.1 Biological and endogenous factors Humans Genetic Predisposition to Disease Aetiology Polymorphism International Genomics of Alzheimer's Project (IGAP) Alleles Parkinson's Disease Neurology & Neurosurgery Prevention Human Genome Psychology and Cognitive Sciences Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Parkinson Disease Single Nucleotide Brain Disorders nervous system diseases International Parkinson's Disease Genomics Consortium (IPDGC) Frontotemporal Dementia Neurological Dementia International FTD-Genomics Consortium (IFGC) Biotechnology Genome-Wide Association Study |
Zdroj: | Journal of neurology, neurosurgery, and psychiatry, vol 88, iss 2 |
DOI: | 10.17863/cam.18708 |
Popis: | 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=2.21×10-12), 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. |
Databáze: | OpenAIRE |
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