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Author Notes:

Rosa Rademakers, Ph.D., Department of Neuroscience, Mayo Clinic, Jacksonville , 4500 San Pablo Road, Jacksonville, FL 32224, Phone: (904) 953-6279, Fax:(904)953-7370, Rademakers.rosa@mayo.edu

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MNS reports grants from Avid Radiopharmaceuticals, grants and personal fees from Axovant Sciences, grants and personal fees from Biogen, grants from Genentech, personal fees from Grifols, grants and personal fees from Eli Lilly, grants from Merck, grants from Pfizer, grants from Roche, personal fees from Sanofi, grants from Suven Life Sciences, grants and personal fees from vTv Therapeutics, and holds stock in Brain Health, Muses Labs, and Versanum, outside the submitted work.

ALB reports grants from US National Institutes of Health, grants from Bluefield Project to Cure Frontotemporal Dementia, grants from CBD Solutions, grants from the Tau Consortium, personal fees from AbbVie, grants from Biogen, grants from Bristol-Myers Squibb, grants from C2N Diagnostics, personal fees from Delos Pharmaceuticals, grants and non-financial support from Eli Lilly, personal fees from Denali Therapeutics, personal fees from Alector, grants from FORUM Pharmaceuticals, grants from Genentech, personal fees from Janssen Pharmaceutica, personal fees from Celgene, grants from Roche, grants from TauRx Therapeutics, personal fees from Merck, personal fees from Novartis, personal fees from Toyama Chemical, personal fees from UCB, grants from the Association for Frontotemporal Degeneration, outside the submitted work.

GMH reports grants from the Australian National Health and Medical Research Council (grant numbers 1037747, 1079679), during the conduct of the study.

ZKW reports grants from the NIH/ National Institute of Neurological Disorders and Stroke (grant number P50 NS072187) during the conduct of the study and RCP reports personal fees from Roche, personal fees from Merck, personal fees from Genentech, personal fees from Biogen, during the conduct of the study.

All other authors declare no conflict of interest related to this study.

Research Funding:

National Institute on Aging; National Institute of Neurological Disorders and Stroke; Canadian Institutes of Health Research; Italian Ministry of Health; UK National Institute for Health Research; National Health and Medical Research Council of Australia; and the French National Research Agency.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences & Neurology
  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • PARKINSONS-DISEASE
  • GDNF FAMILY
  • PROTEIN-LEVELS
  • DEMENTIA
  • TMEM106B
  • THERAPY
  • PLASMA
  • COMMON

Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

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Journal Title:

Lancet Neurology

Volume:

Volume 17, Number 6

Publisher:

, Pages 548-558

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10 −5 ) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10 −16 ), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10 −8 ). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals.

Copyright information:

© 2018 Elsevier Ltd

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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