Predicting White Matter Integrity from Multiple Common Genetic Variants

Abstract

Several common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only a small proportion of the variance in brain microstructure, so we set out to explore their combined effect on the white matter integrity of the corpus callosum. We measured six common candidate singlenucleotide polymorphisms (SNPs) in the COMT, NTRK1, BDNF, ErbB4, CLU, and HFE genes, and investigated their individual and aggregate effects on white matter structure in 395 healthy adult twins and siblings (age: 20-30 years). All subjects were scanned with 4-tesla 94-direction high angular resolution diffusion imaging. When combined using mixed-effects linear regression, a joint model based on five of the candidate SNPs (COMT, NTRK1, ErbB4, CLU, and HFE) explained B6% of the variance in the average fractional anisotropy (FA) of the corpus callosum. This predictive model had detectable effects on FA at 82% of the corpus callosum voxels, including the genu, body, and splenium. Predicting the brain's fiber microstructure from genotypes may ultimately help in early risk assessment, and eventually, in personalized treatment for neuropsychiatric disorders in which brain integrity and connectivity are affected.

Association of brain-derived neurotrophic factor DNA methylation and reduced white matter integrity in the anterior corona radiata in major depression

“…Carballedo et al (2012a) suggested that in their DTI study on MDD, the patients with BDNF Met-allele had a smaller FA in the uncinate fasciculus compared to patients who were homozygous for the Val-allele and healthy subjects carrying the Met-allele. Several studies regarding BDNF genotype also suggested that the genetic variants affect WM integrity in healthy subjects (Chiang et al, 2011;Kohannim et al, 2012;Ziegler et al, 2013). We propose, however, that BDNF DNA methylation and the Val66Met polymorphism modulate predisposition to MDD via different mechanisms.…”

Imaging genetics in obsessive-compulsive disorder: Linking genetic variations to alterations in neuroimaging

“…Therefore, such translational studies that implement genetics and imaging techniques may reveal the etiology of OCD more precisely (MacMaster, 2010). The combination of genetic variants and imaging techniques has recently been explored as a tool for personalized medicine and the specificity of imaging findings (Biffi et al, 2010;Hibar et al, 2011;Kohannim et al, 2012;Meda et al, 2012;Nikolova et al, 2011;Stice et al, 2012). In this systematic review, we present an exploration, to our knowledge for the first time, of the current literature involving imaging genetics in OCD.…”

Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive–compulsive disorder

“…However, genetic markers in genes involved in the dopaminergic (COMT), glutamatergic (GRM3) and neurotrophic (BDNF, NTRK1 and NTRK3) pathways have been recently associated with this WM microstructure measure in healthy subjects and also in patients with schizophrenia or major depression (Braskie et al, , 2013Carballedo et al, 2012;Kohannim et al, 2012;Mounce et al, 2014;Seok et al, 2013;Tost et al, 2013).…”