Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients

Abstract

Context: 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.

Design: 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.

Setting: Inpatients and screened control subjects.

Participants: 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.

Interventions: Blood or saliva samples were collected from each participant for DNA extraction and genotyping.

Main outcome measures: 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.

Figure 1

Association results of NTRK2 with suicide attempt among depressed patients. A, The negative common logarithm of the best genetic model P value of the 65 tagging single-nucleotide polymorphisms (SNPs) obtained in the discovery sample was plotted against the SNP’s chromosome position throughout the NTRK2 locus on chromosome 9q22. The lower horizontal line indicates the nominal significance level of .05; the upper horizontal line, the significance level after correction for multiple comparisons over all tested SNPs and genetic models; asterisks, the 5 SNPs for which association with suicide attempt could be replicated in a larger independent German sample; and Mb, megabases. B, The 5’ to 3’ structures of the most prominent isoforms of NTRK2are depicted and aligned with part A. The boxes and lines show the exon-intron structure of NTRK2. TrkB indicates receptor tyrosine kinase B. C, The r²-based linkage disequilibrium structure overall genotyped tagging SNPs in control subjects of the discovery sample is shown. The genetic information content of NTRK2 spanning across 355 kilobases (kb) can be clustered into 16 D’-based haplotype blocks. D, The linkage disequilibrium (r²) between the 5 SNPs associated with suicide attempt among depressed patients in both German samples is displayed.

Figure 2

Multilocus regression analysis revealed a single-nucleotide polymorphism (SNP)–SNP interaction in suicide attempt (SA). Only the 3 SNPs most strongly associated with SA among depressed patients in the combined sample were included in multilocus modeling to conserve power. In addition to the SNPs’ main effects on risk for SA (Table 3), the ndependent SNPs (Figure 1D) rs10868235 and rs1147198 also showed an nteraction effect on SA. The relative risk for SA is plotted against all genotype combinations of the 2 markers.

Figure 3

Replication of suicide attempt (SA) association in an African American cross-sectional study of nonpsychiatric clinic patients. The 2 tested single-nucleotide polymorphisms, rs1147198 (A) and rs1867283 (B), showed no association with SA in the complete sample (all) but did show association with SA among the subgroup of subjects with an ascertained lifetime diagnosis of major depressive disorder (MDD) for rs1147198 (A) and with trend significance also for rs1867283 (B). The risk alleles were the same as in the German samples (eTable 3). OR indicates odds ratio; CI, confidence interval.