title: Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.
abstract: BACKGROUND
  A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported.
  
  
  OBJECTIVE
  To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci.
  
  
  METHODS
  Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a case-control association design.
  
  
  METHODS
  Inpatients and screened control subjects.
  
  
  METHODS
  The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively.
  
  
  METHODS
  Blood or saliva samples were collected from each participant for DNA extraction and genotyping.
  
  
  METHODS
  Associations of SNPs in BDNF and NTRK2 with SA and MDD.
  
  
  RESULTS
  Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7 x 10(-7) for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1-9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes.
  
  
  CONCLUSIONS
  Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 Munich, Germany. kohlim@mpipsykl.mpg.de
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.forename: Daria
authors.initials: D
authors.lastname: Salyakina
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfennig
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Sonja
authors.initials: S
authors.lastname: Horstmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Menke
authors.forename: Stefan
authors.initials: S
authors.lastname: Kloiber
authors.forename: Johannes
authors.initials: J
authors.lastname: Hennings
authors.forename: Bekh B
authors.initials: BB
authors.lastname: Bradley
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D001741:Black or African American / Q000235:genetics; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D005858:Germany; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D020813:Receptor, trkB / Q000235:genetics*; D012044:Regression Analysis; D012307:Risk Factors; D013406:Suicide, Attempted / Q000523:psychology / Q000706:statistics & numerical data; D014481:United States
chemical_list: D005819:Genetic Markers; D020813:Receptor, trkB