Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in healthy young adults

Abstract

The NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3'-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults is related to common variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain. To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6 ± 2.2 years; range: 20-29 years) with 105-gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) - a DTI measure of white matter integrity. FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p=0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders.

Keywords: BDNF; BPD; Bipolar disorder; DTI; DZ; Diffusion tensor imaging; FA; FDR; FLIRT; FSL's linear image registration tool; FWHM; Fractional anisotropy; HWE; Hardy–Weinberg equilibrium; IFO; ILF and SLF; LD; MAF; MZ; NT3; NTRK1; NTRK3 aka TRKC; OCD; Obsessive–compulsive disorder; SNP; Schizophrenia; Single nucleotide polymorphism; bipolar disorder; brain-derived neurotrophic factor; diffusion tensor imaging; dizygotic; false discovery rate; fractional anisotropy; full-width at half maximum; inferior and superior longitudinal fasciculi; inferior fronto-occipital fasciculus; linkage disequilibrium; minor allele frequencies; monozygotic; neurotrophic tyrosine kinase, receptor, type 1; neurotrophic tyrosine kinase, receptor, type 3 gene; neurotrophin 3′-nucleotidase; obsessive–compulsive disorder; single nucleotide polymorphism.