Rare Variants in Tissue Inhibitor of Metalloproteinase 2 as a Risk Factor for Schizophrenia: Evidence From Familial and Cohort Analysis.

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  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: United States NLM ID: 0236760 Publication Model: Print Cited Medium: Internet ISSN: 1745-1701 (Electronic) Linking ISSN: 05867614 NLM ISO Abbreviation: Schizophr Bull Subsets: MEDLINE
    • Publication Information:
      Publication: 2005- : Cary, NC : Oxford University Press
      Original Publication: [Chevy Chase, Md., For sale by the Supt. of Docs., U. S. Govt. Print. Off. Washington]
    • Subject Terms:
      Genetic Linkage* ; Exome Sequencing*; Schizophrenia/*genetics ; Tissue Inhibitor of Metalloproteinase-2/*genetics; Cohort Studies ; Genetic Variation ; Humans ; India ; Mutation ; Pedigree ; Risk Factors
    • Abstract:
      Candidate gene and genome-wide association study based common risk variant identification is being complemented by whole exome sequencing (WES)/whole genome sequencing based rare variant discovery in elucidation of genetic landscape of schizophrenia (SZ), a common neuropsychiatric disorder. WES findings of de novo mutations in case-parent trios have further implied genetic etiology, but do not explain the high genetic risk in general populations. Conversely, WES in multiplex families may be an insightful strategy for the identification of highly penetrant rare variants in SZ and possibly enhance our understanding of disease biology. In this study, we analyzed a 5-generation Indian family with multiple members affected with SZ by WES. We identified a rare heterozygous missense variant (NM_003255: c.506C>T; p.Pro169Leu; MAF = 0.0001) in Tissue Inhibitor of Metalloproteinase 2 (TIMP2, 17q25.3) segregating with all 6 affected individuals but not with unaffected members. Linkage analysis indicated a maximum logarithm of the odds score of 1.8, θ = 0 at this locus. The variant was predicted to be damaging by various in silico tools and also disrupt the structural integrity by molecular dynamics simulations. WES based screening of an independent SZ cohort (n = 370) identified 4 additional rare missense variants (p.Leu20Met, p.Ala26Ser, p.Lys48Arg and p. Ile217Leu) and a splice variant rs540397728 (NM_003255:c.232-5T>C), also predicted to be damaging, increasing the likelihood of contribution of this gene to SZ risk. Extensive biochemical and knockout mouse studies suggesting involvement of TIMP2 in neurodevelopmental and behavioral deficits, together with genetic evidence for TIMP2 conferring SZ risk from this study may have possible implications for new therapeutics.
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    • Grant Information:
      D43 TW009114 United States TW FIC NIH HHS; R01 MH063480 United States MH NIMH NIH HHS; R01 MH093246 United States MH NIMH NIH HHS
    • Accession Number:
      0 (TIMP2 protein, human)
      127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
    • Publication Date:
      Date Created: 20180201 Date Completed: 20190619 Latest Revision: 20241113
    • Publication Date:
      20241113
    • Accession Number:
      PMC6293225
    • Accession Number:
      10.1093/schbul/sbx196
    • Accession Number:
      29385606