Genetics of Brain Fiber Architecture and Intellectual Performance

Abstract

The study is the first to analyze genetic and environmental factors that affect brain fiber architecture and its genetic linkage with cognitive function. We assessed white matter integrity voxelwise using diffusion tensor imaging at high magnetic field (4 Tesla), in 92 identical and fraternal twins. White matter integrity, quantified using fractional anisotropy (FA), was used to fit structural equation models (SEM) at each point in the brain, generating three-dimensional maps of heritability. We visualized the anatomical profile of correlations between white matter integrity and full-scale, verbal, and performance intelligence quotients (FIQ, VIQ, and PIQ). White matter integrity (FA) was under strong genetic control and was highly heritable in bilateral frontal (a 2 ϭ 0.55, p ϭ 0.04, left; a 2 ϭ 0.74, p ϭ 0.006, right), bilateral parietal (a 2 ϭ 0.85, p Ͻ 0.001, left; a 2 ϭ 0.84, p Ͻ 0.001, right), and left occipital (a 2 ϭ 0.76, p ϭ 0.003) lobes, and was correlated with FIQ and PIQ in the cingulum, optic radiations, superior fronto-occipital fasciculus, internal capsule, callosal isthmus, and the corona radiata ( p ϭ 0.04 for FIQ and p ϭ 0.01 for PIQ, corrected for multiple comparisons). In a cross-trait mapping approach, common genetic factors mediated the correlation between IQ and white matter integrity, suggesting a common physiological mechanism for both, and common genetic determination. These genetic brain maps reveal heritable aspects of white matter integrity and should expedite the discovery of single-nucleotide polymorphisms affecting fiber connectivity and cognition.

Effects of the BDNF Val66Met Polymorphism on White Matter Microstructure in Healthy Adults

“…It has been demonstrated that DTI measures reflect heritable components of brain structure (Chiang et al, 2009;Kochunov et al, 2010), and are useful to delineate potential fiber tracts anomalies related to psychiatric genetic risk variants. Specifically, genetic associations of risk variants for mood disorders with FA in frontolimbic tracts relevant for emotion processing have been repeatedly described (Alexopoulos et al, 2009;Pacheco et al, 2009), as well as associations of schizophrenia risk variants linked to altered neurodevelopment with FA in prefrontal cognitive pathways (McIntosh et al, 2008;Zuliani et al, 2011).…”

“…Consequently, and analogous to clinical and molecular genetics studies, independent replication is important to gain confidence in the validity of reported findings. In order to minimize spurious associations, we used an ethnically homogenous sample and outcome measures such as FA and radial diffusivity (RD) that are known to be heritable (Chiang et al, 2009;Kochunov et al, 2010). We also attempted to apply rigorous methodology during diffusion imaging acquisition and processing by using a cardiac gated sequence, acquiring isotropic voxels (Smith et al, 2007), excluding data affected by motion, correcting for image distortions caused by magnetic susceptibility (Embleton et al, 2010) and using methods to enhance accuracy of normalization in group analyses (Smith et al, 2006).…”

Intelligence and the brain: A model-based approach

“…These approaches have combined structural and functional data (Choi et al, 2008), structural and functional networks (Li et al, 2009;van den Heuvel, Stam, Kahn, & Hulshoff Pol, 2009), and genetic modeling (Chiang et al, 2009). These approaches show that the synthesis of different techniques may be necessary to get a handle on the nature of g and the brain.…”

Predicting White Matter Integrity from Multiple Common Genetic Variants

“…Measures of white matter integrity derived from DTI, such as fractional anisotropy (FA), are highly heritable (Lee et al, 2008;Chiang et al, 2009;Kochunov et al, 2010;Lee et al, 2010;Patel et al, 2010;Chiang et al, 2011b). As such, they may be useful as intermediate measures or 'endophenotypes' (Meyer-Lindenberg and Weinberger, 2006;de Geus et al, 2008;Hall and Smoller, 2010;Marenco and Radulescu, 2010) for assessing genetic influences on the brain.…”

“…We hypothesize that this would help predict brain integrity, as measured by DTI-derived FA, more powerfully than a single-locus genetic test. We focus on the corpus callosum, as it is the largest white matter structure in the brain, easy to examine at the brain's midline, highly heritable (Chiang et al, 2009;Brouwer et al, 2010;Kochunov et al, 2010), and well studied in neurology and psychiatry as the primary commissure connecting the two brain hemispheres (Foong et al, 2000;Alexander et al, 2007). We chose FA as the DTI measure of white matter structure, as it has been shown to have higher heritability than other DTI parameters, such as radial and axial diffusivity (Kochunov et al, 2010).…”