Association between toll-like receptor 2 gene diversity and early-onset bipolar disorder

J Affect Disord. 2014 Aug:165:135-41. doi: 10.1016/j.jad.2014.04.059. Epub 2014 May 4.


Background: Toll-like receptor 2 (TLR2) molecules play a pivotal role in innate immune responses by their ability to recognize and sense a wide repertoire of infectious and endogenous cellular structural elements. Here we evaluated whether genetic variants in TLR2 influence the age of the disease onset in bipolar disorder (BD).

Methods: DNAs from 571 BD patients 229 early-onset (EO-BD) and 342 late-onset (LO-BD) and 199 healthy controls (HC) were analyzed for the following TLR2 polymorphisms: the 5'-UTR -196 to -174 insertion/deletion (ins/del), the intron 1 rs4696480 A/T, and the exon 3 rs3804099 C/T and rs3804100 C/T. PHASE software was used for haplotype reconstruction. Genetic associations were examined using a chi-square test.

Results: We found that the TLR2 rs3804099 TT was significantly more prevalent in EO-BD than in LO-BD patients (corrected p (pc)=0.024). After excluding family history of psychiatric disorders, we also found that the TLR2 rs4696480 TT genotype was significantly more prevalent in EO-BD as compared to LO-BD and controls (pc=0.002 and 0.002). Homozygous state for the insTTT haplotype, carrying the above mentioned risk genotypes, was significantly more frequent in EO-BD than in LO-BD patients (pc=0.007) and in EO-BD without family history of psychiatric disorders as compared to (i) those with positive history (pc=0.03), (ii) with LO-BD without family history (pc=0.001) and (iii) with HC (pc=0.009).

Limitations: Confirmation by replication in independent BD cohorts is warranted.

Conclusions: Our data suggest the potential role of TLR2 genetic variants in the pathogen-mediated susceptibility to BD.

Keywords: Bipolar disorder; Early-onset; Immunogenetics.; Innate immunity; Toll like receptor 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Bipolar Disorder / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Toll-Like Receptor 2 / genetics*
  • Young Adult


  • TLR2 protein, human
  • Toll-Like Receptor 2