Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients.
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.
Kohli
Martin A
MA
Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 Munich, Germany. kohlim@mpipsykl.mpg.de
Salyakina
Daria
D
Pfennig
Andrea
A
Lucae
Susanne
S
Horstmann
Sonja
S
Menke
Andreas
A
Kloiber
Stefan
S
Hennings
Johannes
J
Bradley
Bekh B
BB
Ressler
Kerry J
KJ
Uhr
Manfred
M
Müller-Myhsok
Bertram
B
Holsboer
Florian
F
Binder
Elisabeth B
EB
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
D005819:Genetic Markers; D020813:Receptor, trkB