TY - JOUR
T1 - Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in healthy young adults
AU - Braskie, Meredith N.
AU - Kohannim, Omid
AU - Jahanshad, Neda
AU - Chiang, Ming Chang
AU - Barysheva, Marina
AU - Toga, Arthur W.
AU - Ringman, John M.
AU - Montgomery, Grant W.
AU - McMahon, Katie L.
AU - de Zubicaray, Greig I.
AU - Martin, Nicholas G.
AU - Wright, Margaret J.
AU - Thompson, Paul M.
N1 - Funding Information:
We thank the twins and siblings for their participation. In Brisbane we thank Marlene Grace and Ann Eldridge for twin recruitment, Aiman Al Najjar and other radiographers for scanning, Kerrie McAloney and Daniel Park for research support, and staff in the Molecular Epidemiology Laboratory for DNA sample processing and preparation. This study was supported by the U.S. National Institutes of Health ( R01 HD050735 , EB008432 , EB008281 , EB007813 , and AG040060 to PT), and the National Health and Medical Research Council, Australia ( NHMRC 486682 and 389875). MNB was funded, in part, by the NIH ( P50 AG16570 ) and by the UCLA Easton Consortium for Biomarker and Drug Discovery in Alzheimer's Disease . OK was funded, in part, by a UCLA Dissertation Year Fellowship and by an NIH NRSA Award ( F30 AG041681 ). GIdZ was supported by an ARC Future Fellowship ( FT0991634 ).
PY - 2013/11/5
Y1 - 2013/11/5
N2 - 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.
AB - 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.
KW - Bipolar disorder
KW - Diffusion tensor imaging
KW - Fractional anisotropy
KW - Obsessive-compulsive disorder
KW - Schizophrenia
KW - Single nucleotide polymorphism
UR - http://www.scopus.com/inward/record.url?scp=84879718696&partnerID=8YFLogxK
U2 - 10.1016/j.neuroimage.2013.05.095
DO - 10.1016/j.neuroimage.2013.05.095
M3 - Article
C2 - 23727532
AN - SCOPUS:84879718696
SN - 1053-8119
VL - 82
SP - 146
EP - 153
JO - NeuroImage
JF - NeuroImage
ER -