Raffaele Ferrari1, Yunpeng Wang2, Jana Vandrovcova1,3, Sebastian Guelfi1,3, Aree Witeolar2, Celeste M Karch4, Andrew J Schork5, Chun C Fan5, James B Brewer6,7, Parastoo Momeni8, Gerard D Schellenberg9, William P Dillon10, Leo P Sugrue10, Christopher P Hess10, Jennifer S Yokoyama11, Luke W Bonham11, Gil D Rabinovici11, Bruce L Miller11, Ole A Andreassen2, Anders M Dale5,6,7, John Hardy1, Rahul S Desikan10. 1. Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK. 2. NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 3. Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, UK. 4. Department of Psychiatry, Washington University, St. Louis, Missouri, USA. 5. Department of Cognitive Sciences, University of California, San Diego, La Jolla, California, USA. 6. Department of Radiology, University of California, San Diego, La Jolla, California, USA. 7. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. 8. Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA. 9. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. 10. Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA. 11. Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
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=2.21×10-12), 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. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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