SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
Authors: Barbier Mathieu , Camuzat Agnès , El Hachimi Khalid , Guegan Justine , Rinaldi Daisy , Lattante Serena , Houot Marion , Sánchez-Valle Raquel , Sabatelli Mario , Antonell Anna , Molina-Porcel Laura , Clot Fabienne , Couratier Philippe , van der Ende Emma , van der Zee Julie , Manzoni Claudia , Camu William , Cazeneuve Cécile , Sellal François , Didic Mira , Golfier Véronique , Pasquier Florence , Duyckaerts Charles , Rossi Giacomina , Bruni Amalia C , Alvarez Victoria , Gómez-Tortosa Estrella , de Mendonça Alexandre , Graff Caroline , Masellis Mario , Nacmias Benedetta , Oumoussa Badreddine Mohand , Jornea Ludmila , Forlani Sylvie ,   The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS, Van Deerlin Viviana , Rohrer Jonathan D , Gelpi Ellen , Rademakers Rosa , Van Swieten John , Le Guern Eric , Van Broeckhoven Christine , Ferrari Raffaele , Génin Emmanuelle , Brice Alexis , Le Ber Isabelle 
Published: September 2021

Abstract
The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.