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1.  A Commonly Carried Genetic Variant in the Delta Opioid Receptor Gene, OPRD1, is Associated with Smaller Regional Brain Volumes: Replication in Elderly and Young Populations 
Human brain mapping  2013;35(4):1226-1236.
Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.
PMCID: PMC4046708  PMID: 23427138
neuroimaging; genetics; neurodegeneration; drug addiction; opiates
2.  Test-Retest Reliability of Graph Theory Measures of Structural Brain Connectivity 
The human connectome has recently become a popular research topic in neuroscience, and many new algorithms have been applied to analyze brain networks. In particular, network topology measures from graph theory have been adapted to analyze network efficiency and ‘small-world’ properties. While there has been a surge in the number of papers examining connectivity through graph theory, questions remain about its test-retest reliability (TRT). In particular, the reproducibility of structural connectivity measures has not been assessed. We examined the TRT of global connectivity measures generated from graph theory analyses of 17 young adults who underwent two high-angular resolution diffusion (HARDI) scans approximately 3 months apart. Of the measures assessed, modularity had the highest TRT, and it was stable across a range of sparsities (a thresholding parameter used to define which network edges are retained). These reliability measures underline the need to develop network descriptors that are robust to acquisition parameters.
PMCID: PMC4039303  PMID: 23286144
3.  Genetic clustering on the hippocampal surface for genome-wide association studies 
Imaging genetics aims to discover how variants in the human genome influence brain measures derived from images. Genome-wide association scans (GWAS) can screen the genome for common differences in our DNA that relate to brain measures. In small samples, GWAS has low power as individual gene effects are weak and one must also correct for multiple comparisons across the genome and the image. Here we extend recent work on genetic clustering of images, to analyze surface-based models of anatomy using GWAS. We performed spherical harmonic analysis of hippocampal surfaces, automatically extracted from brain MRI scans of 1254 subjects. We clustered hippocampal surface regions with common genetic influences by examining genetic correlations (rg) between the normalized deformation values at all pairs of surface points. Using genetic correlations to cluster surface measures, we were able to boost effect sizes for genetic associations, compared to clustering with traditional phenotypic correlations using Pearson's r.
PMCID: PMC4024454  PMID: 24579201
heritability; GWAS; clustering; hippocampus; 3D surfaces; imaging genetics
4.  Development of Insula Connectivity Between Ages 12 and 30 Revealed by High Angular Resolution Diffusion Imaging 
Human brain mapping  2013;35(4):1790-1800.
The insula, hidden deep within the Sylvian fissures, has proven difficult to study from a connectivity perspective. Most of our current information on the anatomical connectivity of the insula comes from studies of nonhuman primates and post mortem human dissections. To date, only two neuroimaging studies have successfully examined the connectivity of the insula. Here we examine how the connectivity of the insula develops between ages 12 and 30, in 307 young adolescent and adult subjects scanned with 4-Tesla high angular resolution diffusion imaging (HARDI). The density of fiber connections between the insula and the frontal and parietal cortex decreased with age, but the connection density between the insula and the temporal cortex generally increased with age. This trajectory is in line with well-known patterns of cortical development in these regions. In addition, males and females showed different developmental trajectories for the connection between the left insula and the left precentral gyrus. The insula plays many different roles, some of them affected in neuropsychiatric disorders; this information on the insula's connectivity may help efforts to elucidate mechanisms of brain disorders in which it is implicated.
PMCID: PMC4017914  PMID: 23836455
insula; development; tractography; HARDI; structural connectivity
The ‘rich club’ coefficient describes a phenomenon where a network's hubs (high-degree nodes) are on average more intensely interconnected than lower-degree nodes. Networks with rich clubs often have an efficient, higher-order organization, but we do not yet know how the rich club emerges in the living brain, or how it changes as our brain networks develop. Here we chart the developmental trajectory of the rich club in anatomical brain networks from 438 subjects aged 12-30. Cortical networks were constructed from 68×68 connectivity matrices of fiber density, using whole-brain tractography in 4-Tesla 105-gradient high angular resolution diffusion images (HARDI). The adult and younger cohorts had rich clubs that included different nodes; the rich club effect intensified with age. Rich-club organization is a sign of a network's efficiency and robustness. These concepts and findings may be advantageous for studying brain maturation and abnormal brain development.
PMCID: PMC4017916  PMID: 24827471
rich club coefficient; high angular resolution diffusion imaging (HARDI); tractography; network analyses; development; structural connectivity
6.  Genetic effects on the cerebellar role in working memory: Same brain, different genes? 
NeuroImage  2013;86:392-403.
Over the past several years, evidence has accumulated showing that the cerebellum plays a significant role in cognitive function. Here we show, in a large genetically informative twin sample (n = 430; aged 16–30 years), that the cerebellum is strongly, and reliably (n = 30 rescans), activated during an n-back working memory task, particularly lobules I–IV, VIIa Crus I and II, IX and the vermis. Monozygotic twin correlations for cerebellar activation were generally much larger than dizygotic twin correlations, consistent with genetic influences. Structural equation models showed that up to 65% of the variance in cerebellar activation during working memory is genetic (averaging 34% across significant voxels), most prominently in the lobules VI, and VIIa Crus I, with the remaining variance explained by unique/unshared environmental factors. Heritability estimates for brain activation in the cerebellum agree with those found for working memory activation in the cerebral cortex, even though cerebellar cyto-architecture differs substantially. Phenotypic correlations between BOLD percent signal change in cerebrum and cerebellum were low, and bivariate modeling indicated that genetic influences on the cerebellum are at least partly specific to the cerebellum. Activation on the voxel-level correlated very weakly with cerebellar gray matter volume, suggesting specific genetic influences on the BOLD signal. Heritable signals identified here should facilitate discovery of genetic polymorphisms influencing cerebellar function through genome-wide association studies, to elucidate the genetic liability to brain disorders affecting the cerebellum.
PMCID: PMC3925745  PMID: 24128737
Cerebellum; Heritability; Genetics; Functional MRI; Working memory; Twin study
7.  Development of Brain Structural Connectivity between Ages 12 and 30: A 4-Tesla Diffusion Imaging Study in 439 Adolescents and Adults 
NeuroImage  2012;64:671-684.
Understanding how the brain matures in healthy individuals is critical for evaluating deviations from normal development in psychiatric and neurodevelopmental disorders. The brain’s anatomical networks are profoundly re-modeled between childhood and adulthood, and diffusion tractography offers unprecedented power to reconstruct these networks and neural pathways in vivo. Here we tracked changes in structural connectivity and network efficiency in 439 right-handed individuals aged 12 to 30 (211 female/126 male adults, mean age=23.6, SD=2.19; 31 female/24 male 12 year olds, mean age=12.3, SD=0.18; and 25 female/22 male 16 year olds, mean age=16.2, SD=0.37). All participants were scanned with high angular resolution diffusion imaging (HARDI) at 4 Tesla. After we performed whole brain tractography, 70 cortical gyral-based regions of interest were extracted from each participant’s co-registered anatomical scans. The degree of fiber connections between all pairs of cortical regions, or nodes, were found to create symmetric fiber density matrices, reflecting the structural brain network. From those 70×70 matrices we computed graph theory metrics characterizing structural connectivity. Several key global and nodal metrics changed across development, showing increased network integration, with some connections pruned and others strengthened. The increases and decreases in fiber density, however, were not distributed proportionally across the brain. The frontal cortex had a disproportionate number of decreases in fiber density while the temporal cortex had a disproportionate number of increases in fiber density. This large-scale analysis of the developing structural connectome offers a foundation to develop statistical criteria for aberrant brain connectivity as the human brain matures.
PMCID: PMC3603574  PMID: 22982357
HARDI; structural connectivity; graph theory; development
8.  Alzheimer’s Disease Risk Gene, GAB2, is Associated with Regional Brain Volume Differences in 755 Young Healthy Twins 
The development of late-onset Alzheimer’s disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer’s disease risk gene, growth factor receptor bound protein 2-associated protein (GAB2), has been shown to provide a 1.27–1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young-adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young-adult twins (469 females) (M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer’s disease.
PMCID: PMC3785377  PMID: 22856364
GAB2; imaging genetics; tensor-based morphometry; Alzheimer’s disease
9.  Predicting White Matter Integrity from Multiple Common Genetic Variants 
Neuropsychopharmacology  2012;37(9):2012-2019.
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 single-nucleotide 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 ∼6% 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.
PMCID: PMC3398730  PMID: 22510721
neuroimaging; brain structure; DTI; genetics; genetic profiles; prediction; imaging; clinical or preclinical; neuroanatomy; neurogenetics; pharmacogenetics / pharmacogenomics; neuroimaging; brain structure; DTI; genetics; genetic profiles
10.  Hierarchical topological network analysis of anatomical human brain connectivity and differences related to sex and kinship 
NeuroImage  2011;59(4):3784-3804.
Modern non-invasive brain imaging technologies, such as diffusion weighted magnetic resonance imaging (DWI), enable the mapping of neural fiber tracts in the white matter, providing a basis to reconstruct a detailed map of brain structural connectivity networks. Brain connectivity networks differ from random networks in their topology, which can be measured using small worldness, modularity, and high-degree nodes (hubs). Still, little is known about how individual differences in structural brain network properties relate to age, sex, or genetic differences. Recently, some groups have reported brain network biomarkers that enable differentiation among individuals, pairs of individuals, and groups of individuals. In addition to studying new topological features, here we provide a unifying general method to investigate topological brain networks and connectivity differences between individuals, pairs of individuals, and groups of individuals at several levels of the data hierarchy, while appropriately controlling false discovery rate (FDR) errors. We apply our new method to a large dataset of high quality brain connectivity networks obtained from High Angular Resolution Diffusion Imaging (HARDI) tractography in 303 young adult twins, siblings, and unrelated people. Our proposed approach can accurately classify brain connectivity networks based on sex (93% accuracy) and kinship (88.5% accuracy). We find statistically significant differences associated with sex and kinship both in the brain connectivity networks and in derived topological metrics, such as the clustering coefficient and the communicability matrix.
PMCID: PMC3551467  PMID: 22108644
Anatomical brain connectivity; Complex networks; Diffusion weighted MRI; Topological analysis; Hierarchical analysis; False discovery rate; Sex and kinship brain network differences
Large multi-site image-analysis studies have successfully discovered genetic variants that affect brain structure in tens of thousands of subjects scanned worldwide. Candidate genes have also associated with brain integrity, measured using fractional anisotropy in diffusion tensor images (DTI). To evaluate the heritability and robustness of DTI measures as a target for genetic analysis, we compared 417 twins and siblings scanned on the same day on the same high field scanner (4-Tesla) with two protocols: (1) 94-directions; 2mm-thick slices, (2) 27-directions; 5mm-thickness. Using mean FA in white matter ROIs and FA ‘skeletons’ derived using FSL, we (1) examined differences in voxelwise means, variances, and correlations among the measures; and (2) assessed heritability with structural equation models, using the classical twin design. FA measures from the genu of the corpus callosum were highly heritable, regardless of protocol. Genome-wide analysis of the genu mean FA revealed differences across protocols in the top associations.
PMCID: PMC3420973  PMID: 22903274
imaging genetics; DTI protocol stability; corpus callosum; genome-wide association study; multi-site analysis
Graph theory can be applied to matrices that represent the brain’s anatomical connections, to better understand global properties of anatomical networks, such as their clustering, efficiency and “small-world” topology. Network analysis is popular in adult studies of connectivity, but only one study – in just 30 subjects – has examined how network measures change as the brain develops over this period. Here we assessed the developmental trajectory of graph theory metrics of structural brain connectivity in a cross-sectional study of 467 subjects, aged 12 to 30. We computed network measures from 70×70 connectivity matrices of fiber density generated using whole-brain tractography in 4-Tesla 105-gradient high angular resolution diffusion images (HARDI). We assessed global efficiency and modularity, and both age and age2 effects were identified. HARDI-based connectivity maps are sensitive to the remodeling and refinement of structural brain connections as the human brain develops.
PMCID: PMC3420974  PMID: 22903354
graph theory; high angular resolution diffusion imaging (HARDI); tractography; network analyses; development; structural connectivity
Human brain connectivity is disrupted in a wide range of disorders – from Alzheimer’s disease to autism – but little is known about which specific genes affect it. Here we conducted a genome-wide association for connectivity matrices that capture information on the density of fiber connections between 70 brain regions. We scanned a large twin cohort (N=366) with 4-Tesla high angular resolution diffusion imaging (105-gradient HARDI). Using whole brain HARDI tractography, we extracted a relatively sparse 70×70 matrix representing fiber density between all pairs of cortical regions automatically labeled in co-registered anatomical scans. Additive genetic factors accounted for 1–58% of the variance in connectivity between 90 (of 122) tested nodes. We discovered genome-wide significant associations between variants and connectivity. GWAS permutations at various levels of heritability, and split-sample replication, validated our genetic findings. The resulting genes may offer new leads for mechanisms influencing aberrant connectivity and neurodegeneration.
PMCID: PMC3420975  PMID: 22903411
genetics; high angular resolution diffusion imaging (HARDI); cortical surfaces; twin modeling; human connectome
A major challenge in neuroscience is finding which genes affect brain integrity, connectivity, and intellectual function. Discovering influential genes holds vast promise for neuroscience, but typical genome-wide searches assess around one million genetic variants one-by-one, leading to intractable false positive rates, even with vast samples of subjects. Even more intractable is the question of which genes interact and how they work together to affect brain connectivity. Here we report a novel approach that discovers which genes contribute to brain wiring and fiber integrity at all pairs of points in a brain scan. We studied genetic correlations between thousands of points in human brain images from 472 twins and their non-twin siblings (mean age: 23.7±2.1 SD years; 193 M/279 F). We combined clustering with genome-wide scanning to find brain systems with common genetic determination. We then filtered the image in a new way to boost power to find causal genes. Using network analysis, we found a network of genes that affect brain wiring in healthy young adults. Our new strategy makes it more computationally tractable to discover genes that affect brain integrity. The gene network showed small-world and scale-free topologies, suggesting efficiency in genetic interactions, and resilience to network disruption. Genetic variants at hubs of the network influence intellectual performance by modulating associations between performance intelligence quotient (IQ) and the integrity of major white matter tracts, such as the callosal genu and splenium, cingulum, optic radiations, and the superior longitudinal fasciculus.
PMCID: PMC3420968  PMID: 22723713
imaging genetics; twins; white matter; diffusion imaging; intelligence quotient; scale-free network; small-world network
15.  Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene, CNTNAP2 
Brain Connectivity  2011;1(6):447-459.
Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here, we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 women, 119 men, age: 23.4±2.17 SD years) were scanned with 105-gradient high-angular-resolution diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual's co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole-brain analyses, and lower eccentricity (maximum path length) in 60 of the 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study that links graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of the circuits implicated in the risk for autism.
PMCID: PMC3420970  PMID: 22500773
autism; CNTNAP2; graph theory; HARDI; structural connectivity; twins
16.  Relationship of a variant in the NTRK1 gene to white matter microstructure in young adults 
The Journal of Neuroscience  2012;32(17):5964-5972.
The NTRK1 gene (also known as TRKA) encodes a high affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower FA in healthy adults.
We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 ± 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 Tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy – a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test results reproducibility. The false discovery rate method corrected for voxelwise multiple comparisons.
NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure.
PMCID: PMC3393752  PMID: 22539856
17.  How a common variant in the growth factor receptor gene, NTRK1, affects white matter 
Bioarchitecture  2012;2(5):181-184.
Growth factors and their receptors are important for cellular migration as well as axonal guidance and myelination in the brain. They also play a key role in programmed cell death, and are implicated in a number of mental illnesses. Recently, we reported that healthy young adults who carry the T allele variant in the growth factor gene, NTRK1 (at location rs6336), had lower white matter integrity than non-carriers on diffusion images of the brain. Diffusion tensor imaging (DTI) revealed how this single nucleotide polymorphism affects white matter microstructure in human populations; DTI is also used to identify characteristic features of brain connectivity in typically developing children and in patients. Newly discovered links between neuroimaging measures and growth factors whose molecular neuroscience is well known offer an important step in understanding mechanisms that contribute to brain connectivity. Altered fiber connectivity may mediate the relationship between some genetic risk factors and a variety of mental illnesses.
PMCID: PMC3696063  PMID: 22986407
neurotrophin; growth factor; tropomyosin-related kinase receptor A; neurotrophic tyrosine kinase receptor 1; myelin; development; fractional anisotropy; radial diffusivity; diffusion tensor imaging; schizophrenia
18.  Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene, CNTNAP2 
Brain connectivity  2011;1(6):447-459.
Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 females, 119 males, age: 23.4 +/−2.17 SD years) were scanned with 105-gradient high angular diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual’s co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole brain analyses, as well as greater eccentricity (maximum path length) in 60 of 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study to link graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of circuits implicated in risk for autism.
PMCID: PMC3420970  PMID: 22500773
structural connectivity; HARDI; autism; CNTNAP2; graph theory; twins
19.  Neural mechanisms underlying the facilitation of naming in aphasia using a semantic task: an fMRI study 
BMC Neuroscience  2012;13:98.
Previous attempts to investigate the effects of semantic tasks on picture naming in both healthy controls and people with aphasia have typically been confounded by inclusion of the phonological word form of the target item. As a result, it is difficult to isolate any facilitatory effects of a semantically-focused task to either lexical-semantic or phonological processing. This functional magnetic resonance imaging (fMRI) study examined the neurological mechanisms underlying short-term (within minutes) and long-term (within days) facilitation of naming from a semantic task that did not include the phonological word form, in both participants with aphasia and age-matched controls.
Behavioral results showed that a semantic task that did not include the phonological word form can successfully facilitate subsequent picture naming in both healthy controls and individuals with aphasia. The whole brain neuroimaging results for control participants identified a repetition enhancement effect in the short-term, with modulation of activity found in regions that have not traditionally been associated with semantic processing, such as the right lingual gyrus (extending to the precuneus) and the left inferior occipital gyrus (extending to the fusiform gyrus). In contrast, the participants with aphasia showed significant differences in activation over both the short- and the long-term for facilitated items, predominantly within either left hemisphere regions linked to semantic processing or their right hemisphere homologues.
For control participants in this study, the short-lived facilitation effects of a prior semantic task that did not include the phonological word form were primarily driven by object priming and episodic memory mechanisms. However, facilitation effects appeared to engage a predominantly semantic network in participants with aphasia over both the short- and the long-term. The findings of the present study also suggest that right hemisphere involvement may be supportive rather than maladaptive, and that a large distributed perisylvian network in both cerebral hemispheres supports the facilitation of naming in individuals with aphasia.
PMCID: PMC3477078  PMID: 22882806
Aphasia; Semantic verification; fMRI; Overt picture naming; Semantics
NeuroImage  2010;55(2):448-454.
Brain-derived neurotrophic factor (BDNF) plays a key role in learning and memory, but its effects on the fiber architecture of the living brain are unknown. We genotyped 455 healthy adult twins and their non-twin siblings (188 males/267 females; age: 23.7±2.1 years, mean±SD) and scanned them with high angular resolution diffusion tensor imaging (DTI), to assess how the BDNF Val66Met polymorphism affects white matter microstructure. By applying genetic association analysis to every 3D point in the brain images, we found that the Val-BDNF genetic variant was associated with lower white matter integrity in the splenium of the corpus callosum, left optic radiation, inferior fronto-occipital fasciculus, and superior corona radiata. Normal BDNF variation influenced the association between subjects’ performance intellectual ability (as measured by Object Assembly subtest) and fiber integrity (as measured by fractional anisotropy; FA) in the callosal splenium, and pons. The BDNF gene may affect intellectual performance by modulating white matter development. This combination of genetic association analysis and large-scale diffusion imaging directly relates a specific gene to the fiber microstructure of the living brain and to human intelligence.
PMCID: PMC3192852  PMID: 21195196
BDNF; twins; diffusion imaging; cognition; imaging genomics; white matter
21.  Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search 
Molecular psychiatry  2011;16(9):927-881.
The caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders. To identify specific genes associated with variations in caudate volume, structural MRI and genome-wide genotypes were acquired from two large cohorts, the Alzheimer’s Disease NeuroImaging Initiative (ADNI; N=734) and the Brisbane Adolescent/Young Adult Longitudinal Twin Study (BLTS; N=464). In a preliminary analysis of heritability, around 90% of the variation in caudate volume was due to genetic factors. We then conducted genome-wide association to find common variants that contribute to this relatively high heritability. Replicated genetic association was found for the right caudate volume at SNP rs163030 in the ADNI discovery sample (P=2.36×10−6) and in the BLTS replication sample (P=0.012). This genetic variation accounted for 2.79% and 1.61% of the trait variance, respectively. The peak of association was found in and around two genes, WDR41 and PDE8B, involved in dopamine signaling and development. In addition, a previously identified mutation in PDE8B causes a rare autosomal-dominant type of striatal degeneration. Searching across both samples offers a rigorous way to screen for genes consistently influencing brain structure at different stages of life. Variants identified here may be relevant to common disorders affecting the caudate.
PMCID: PMC3140560  PMID: 21502949
genome-wide association; dopamine; caudate; heritability; WDR41; PDE8B (3-6 needed)
22.  The Contribution of Genes to Cortical Thickness and Volume 
Neuroreport  2011;22(3):101-105.
We analyzed brain MRI data from 372 young adult twins to identify cortical regions in which gray matter thickness and volume are influenced by genetics. This was achieved using a A/C/E structural equation model that divides the variance of these traits, at each point on the cortex, into additive genetic (A), shared (C) and unique environmental (E) components. A strong genetic influence was found in frontal and parietal regions. Additionally, we correlated cortical thickness with full-scale IQ for comparison with the A/C/E maps, and several regions where cortical structure was correlated with IQ are under genetic control. These cortical measures may be useful phenotypes to narrow the search for quantitative trait loci influencing brain structure.
PMCID: PMC3079384  PMID: 21233781
brain; image analysis; magnetic resonance imaging; cortex; genetics
NeuroImage  2010;54(3):2308-2317.
White matter microstructure is under strong genetic control, yet it is largely unknown how genetic influences change from childhood into adulthood. In one of the largest brain mapping studies ever performed, we determined whether the genetic control over white matter architecture depends on age, sex, socioeconomic status (SES), and intelligence quotient (IQ). We assessed white matter integrity voxelwise using diffusion tensor imaging at high magnetic field (4-Tesla), in 705 twins and their siblings (age range 12–29; 290 M/415 F). White matter integrity was quantified using a widely accepted measure, fractional anisotropy (FA). We fitted gene-environment interaction models pointwise, to visualize brain regions where age, sex, SES and IQ modulate heritability of fiber integrity. We hypothesized that environmental factors would start to outweigh genetic factors during late childhood and adolescence. Genetic influences were greater in adolescence versus adulthood, and greater in males than in females. Socioeconomic status significantly interacted with genes that affect fiber integrity: heritability was higher in those with higher SES. In people with above-average IQ, genetic factors explained over 800% of the observed FA variability in the thalamus, genu, posterior internal capsule, and superior corona radiata. In those with below-average IQ, however, only around 40% FA variability in the same regions was attributable to genetic factors. Genes affect fiber integrity, but their effects vary with age, sex, SES and IQ. Gene-environment interactions are vital to consider in the search for specific genetic polymorphisms that affect brain integrity and connectivity.
PMCID: PMC3197836  PMID: 20950689
genetics; cognition; twins; white matter; diffusion imaging; gene-environment interaction
24.  Heritability of working memory brain activation 
Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean age 23.6±1.8 S.D.) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at high magnetic field (4 Tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0-back) were significantly heritable, with the highest estimates (40 – 65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, pre- and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that non-genetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders.
PMCID: PMC3163233  PMID: 21795540
twin study; heritability; genetic modeling; functional MRI; working memory; voxel-based analysis
25.  Discovery and Replication of Gene Influences on Brain Structure Using LASSO Regression 
We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2. We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8 ± 2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain.
PMCID: PMC3412288  PMID: 22888310
neuroimaging; MRI; imaging genetics; GWAS; LASSO; MACROD2

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