TY - JOUR
T1 - Linkage Disequilibrium Mapping of a Chromosome 15q25-26 Major Depression Linkage Region and Sequencing of NTRK3
AU - Verma, Ranjana
AU - Holmans, Peter
AU - Knowles, James A.
AU - Grover, Deepak
AU - Evgrafov, Oleg V.
AU - Crowe, Raymond R.
AU - Scheftner, William A.
AU - Weissman, Myrna M.
AU - DePaulo, J. Raymond
AU - Potash, James B.
AU - Levinson, Douglas F.
N1 - Funding Information:
This work was supported by National Institute of Mental Health (NIMH) Grant Nos. 5R01MH059542 (RC), 5R01MH059552 (JRD/JBP), 5R01MH061686 and 1K24MH64197 (DFL), 5R01MH059541 (WAS), and 5R01MH060912 (MMW). The GenRED cell and data collections used in this study included contributions from Dr. George S. Zubenko and Dr. Wendy N. Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, that were supported by R01 Grant No. MH60866 from the NIMH (GSZ, PI). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to Johns Hopkins University, Contract No. N01-HG-65403. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Thanks to Barbara Schweizer, Brandie Craighead, and Jennifer Toolan for their assistance. The authors express their profound appreciation to the families who participated in this project and to the many clinicians who facilitated the referral of participants to the study. Data and biomaterials were collected in six projects that participated in the NIMH Genetics of Recurrent Early-Onset Depression (GenRED) project. From 1999 to 2003, the Principal Investigators and Co-Investigators were as follows: New York State Psychiatric Institute, New York, NY, R01 MH060912 , Myrna M. Weissman, PhD, and James K. Knowles, MD, PhD; University of Pittsburgh, Pittsburgh, PA, R01 MH060866 , George S. Zubenko, MD, PhD, and Wendy N. Zubenko, EdD, RN, CS; Johns Hopkins University, Baltimore, R01 MH059552 , J. Raymond DePaulo, MD, Melvin G. McInnis, MD, and Dean MacKinnon, MD; University of Pennsylvania, Philadelphia, PA, RO1 MH61686, Douglas F. Levinson, MD (GenRED coordinator), Madeleine M. Gladis, PhD, Kathleen Murphy-Eberenz, PhD, and Peter Holmans, PhD (University of Wales College of Medicine); University of Iowa, Iowa City, IA, R01 MH059542 , Raymond R. Crowe, MD, and William H. Coryell, MD; Rush University Medical Center, Chicago, IL, R01 MH059541 -05, William A. Scheftner, MD, Rush-Presbyterian. Control subjects from the NIMH Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the Molecular Genetics of Schizophrenia II (MGS-2) collaboration. The investigators and coinvestigators are as follows: ENH/Northwestern University, Evanston, IL, MH059571 , Pablo V. Gejman, MD (Collaboration Coordinator; PI), Alan R. Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587, Farooq Amin, MD (PI); Louisiana State University Health Sciences Center, New Orleans, Louisiana, MH067257 , Nancy Buccola APRN, BC, MSN (PI); University of California—Irvine, Irvine, CA, MH60870, William Byerley, MD (PI); Washington University, St. Louis, MO, U01, MH060879 , C. Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566, Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565 , Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675 , Douglas Levinson MD (PI); University of Queensland, Queensland, Australia, MH059588 , Bryan Mowry, MD (PI); Mt. Sinai School of Medicine, New York, NY, MH59586, Jeremy Silverman, PhD (PI).
Funding Information:
Dr. Weissman received investigator-initiated grants from Lilly and GlaxoSmithkline. Drs. Verma, Grover, Holmans, Knowles, Grover, Evgrafov, Crowe, Scheftner, DePaulo, and Potash reported no biomedical financial interests or potential conflicts of interest.
PY - 2008/6/15
Y1 - 2008/6/15
N2 - 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.
AB - 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.
KW - Association
KW - TRKC
KW - major depression
KW - neurotrophin NTRK3
KW - tag SNPs
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U2 - 10.1016/j.biopsych.2008.02.005
DO - 10.1016/j.biopsych.2008.02.005
M3 - Article
C2 - 18367154
AN - SCOPUS:44349182092
SN - 0006-3223
VL - 63
SP - 1185
EP - 1189
JO - Biological psychiatry
JF - Biological psychiatry
IS - 12
ER -