TY - JOUR
T1 - A Whole-Genome Sequencing Study Implicates GRAMD1B in Multiple Sclerosis Susceptibility
AU - Esposito, Federica
AU - Osiceanu, Ana Maria
AU - Sorosina, Melissa
AU - Ottoboni, Linda
AU - Bollman, Bryan
AU - Santoro, Silvia
AU - Bettegazzi, Barbara
AU - Zauli, Andrea
AU - Clarelli, Ferdinando
AU - Mascia, Elisabetta
AU - Calabria, Andrea
AU - Zacchetti, Daniele
AU - Capra, Ruggero
AU - Ferrari, Maurizio
AU - Provero, Paolo
AU - Lazarevic, Dejan
AU - Cittaro, Davide
AU - Carrera, Paola
AU - Patsopoulos, Nikolaos
AU - Toniolo, Daniela
AU - Sadovnick, A. Dessa
AU - Martino, Gianvito
AU - De Jager, Philip L.
AU - Comi, Giancarlo
AU - Stupka, Elia
AU - Vilariño-Güell, Carles
AU - Piccio, Laura
AU - Martinelli Boneschi, Filippo
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/12
Y1 - 2022/12
N2 - While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology.
AB - While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology.
KW - multiple sclerosis
KW - neurology
KW - rare variants
KW - sequencing
UR - https://www.scopus.com/pages/publications/85144487399
U2 - 10.3390/genes13122392
DO - 10.3390/genes13122392
M3 - Article
C2 - 36553660
AN - SCOPUS:85144487399
SN - 2073-4425
VL - 13
JO - Genes
JF - Genes
IS - 12
M1 - 2392
ER -