Linkage Disequilibrium Mapping of a Chromosome 15q25-26 Major Depression Linkage Region and Sequencing of NTRK3

Ranjana Verma, Peter Holmans, James A. Knowles, Deepak Grover, Oleg V. Evgrafov, Raymond R. Crowe, William A. Scheftner, Myrna M. Weissman, J. Raymond DePaulo, James B. Potash, Douglas F. Levinson

Research output: Contribution to journalArticle

Abstract

Background: We reported genome-wide significant linkage on chromosome 15q25.3-26.2 to recurrent early-onset major depressive disorder (MDD-RE). Here we present initial linkage-disequilibrium (LD) fine mapping of this signal and sequence analysis of NTRK3 (neurotrophic receptor kinase-3), a biologically plausible candidate gene. Methods: In 300 pedigrees informative for family-based association, 1195 individuals were genotyped for 795 single nucleotide polymorphism (SNPs). We resequenced 21 exons and 7 highly conserved NTRK3 regions in 176 MDD-RE cases to test for an excess of rare functional variants and, 176 controls for case-control analysis of common variants. Results: LD mapping showed nominally significant association in NTRK3, FLJ12484, RHCG, DKFZp547K1113, VPS33B, SV2B, SLCO3A1, RGMA, and MCTP2 with MDD-RE. In NTRK3, five SNPs had nominally significant p values (.035-.001). Sequence analysis revealed 35 variants (24 novel, including 9 rare exonic); the number of rare variants did not exceed chance expectation. Case-control analysis of 13 common variants showed modest nominal association of MDD-RE with rs4887379, rs6496463, and rs3825882 (p = .008, .048, and .034), which were in partial LD with four of five associated SNPs from the family-based experiment. Conclusions: Common variants in NTRK3 or other genes identified might play a role in MDD-RE. However, much larger studies are required for full evaluation of this region.

Original languageEnglish (US)
Pages (from-to)1185-1189
Number of pages5
JournalBiological psychiatry
Volume63
Issue number12
DOIs
StatePublished - Jun 15 2008

Keywords

  • Association
  • TRKC
  • major depression
  • neurotrophin NTRK3
  • tag SNPs

ASJC Scopus subject areas

  • Biological Psychiatry

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    Verma, R., Holmans, P., Knowles, J. A., Grover, D., Evgrafov, O. V., Crowe, R. R., Scheftner, W. A., Weissman, M. M., DePaulo, J. R., Potash, J. B., & Levinson, D. F. (2008). Linkage Disequilibrium Mapping of a Chromosome 15q25-26 Major Depression Linkage Region and Sequencing of NTRK3. Biological psychiatry, 63(12), 1185-1189. https://doi.org/10.1016/j.biopsych.2008.02.005