TY - JOUR
T1 - Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis
AU - Horjus, Julia
AU - van Mourik-Banda, Tineke
AU - Heerings, Marco A. P.
AU - Hakobjan, Marina
AU - de Witte, Ward
AU - Heersema, Dorothea J.
AU - Jansen, Anne J.
AU - Strijbis, Eva M. M.
AU - de Jong, Brigit A.
AU - Slettenaar, Astrid E. J.
AU - Zeinstra, Esther M. P. E.
AU - Hoogervorst, Erwin L. J.
AU - Franke, Barbara
AU - Kruijer, Wiebe
AU - Jongen, Peter J.
AU - Visser, Leo J.
AU - Poelmans, Geert
N1 - Funding Information: This work was supported by the National MS Foundation, The Netherlands (project number: R0003985; foundation/ANBI status number: 802995184). Publisher Copyright: © 2022 by the authors.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.
AB - Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.
KW - genetics
KW - multiple sclerosis (MS)
KW - whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85139969905&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms231911461
DO - https://doi.org/10.3390/ijms231911461
M3 - Article
C2 - 36232761
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 19
M1 - 11461
ER -