Investigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation

dc.contributor.authorEverest, Elif
dc.contributor.authorAhangari, Mohammad
dc.contributor.authorUygunoglu, Ugur
dc.contributor.authorTutuncu, Melih
dc.contributor.authorBulbul, Alper
dc.contributor.authorSaip, Sabahattin
dc.contributor.authorDuman, Taskin
dc.contributor.authorSezerman, Ugur
dc.contributor.authorReich, Daniel S.
dc.contributor.authorRiley, Brien P.
dc.contributor.authorSiva, Aksel
dc.contributor.authorTuranli, Eda Tahir
dc.date.accessioned2023-02-21T12:39:39Z
dc.date.available2023-02-21T12:39:39Z
dc.date.issued2022-01-01
dc.description.abstractMany multiple sclerosis (MS)-associated common risk variants as well as candidate low-frequency and rare variants have been identified
dc.description.abstracthowever, approximately half of MS heritability remains unexplained. We studied seven multiplex MS families, six of which with parental consanguinity, to identify genetic factors that increase MS risk. Candidate genomic regions were identified through linkage analysis and homozygosity mapping, and fully penetrant, rare, and low-frequency variants were detected by exome sequencing. Weighted sum score and polygenic risk score (PRS) analyses were conducted in MS families (24 affected, 17 unaffected), 23 sporadic MS cases, 63 individuals in 19 non-MS control families, and 1272 independent, ancestry-matched controls. We found that familial MS cases had a significantly higher common risk variation burden compared with population controls and control families. Sporadic MS cases tended to have a higher PRS compared with familial MS cases, suggesting the presence of a higher rare risk variation burden in the families. In line with this, score distributions among affected and unaffected family members within individual families showed that known susceptibility alleles can explain disease development in some high-risk multiplex families, while in others, additional genetic contributors increase MS risk.
dc.description.issue1
dc.description.issueOCT 10
dc.description.volume12
dc.identifier.doi10.1038/s41598-022-21484-x
dc.identifier.urihttps://hdl.handle.net/11443/2530
dc.identifier.urihttp://dx.doi.org/10.1038/s41598-022-21484-x
dc.identifier.wosWOS:000865806900037
dc.publisherNATURE PORTFOLIO
dc.relation.ispartofSCIENTIFIC REPORTS
dc.titleInvestigating the role of common and rare variants in multiplex multiple sclerosis families reveals an increased burden of common risk variation
dc.typeArticle

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