Large-scale GWAS reveals genetic architecture of brain white matter microstructure and genetic overlap with cognitive and mental health traits (n = 17,706)

AbstractSeveral neuroimaging studies have reported associations between brain white matter microstructure and chronotype. However, it is unclear whether those phenotypic relationships are causal or underlined by genetic factors. In the present study, we use genetic data to examine the genetic overlap and infer causal relationships between chronotype and diffusion tensor imaging (DTI) measures. We identify 29 significant pairwise genetic correlations, of which 13 also show evidence for a causal association. Genetic correlations were identified between chronotype and brain-wide mean, axial and radial diffusivities. When exploring individual tracts, 10 genetic correlations were observed with mean diffusivity, 10 with axial diffusivity, 4 with radial diffusivity and 2 with mode of anisotropy. We found evidence for a possible causal association of eveningness with white matter microstructure measures in individual tracts including the posterior limb and the retrolenticular part of the internal capsule; the genu and splenium of the corpus callosum and the posterior, superior and anterior regions of the corona radiata. Our findings contribute to the understanding of how genes influence circadian preference and brain white matter and provide a new avenue for investigating the role of chronotype in health and disease.

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Evidence of genetic overlap between circadian preference and brain white matter microstructure

10.1101/2020.11.09.374199 ◽

2020 ◽

Author(s):

Luis M. García-Marín ◽

Sarael Alcauter ◽

Adrian I. Campos ◽

Aoibhe Mulcahy ◽

Pik-Fang Kho ◽

...

Keyword(s):

White Matter ◽

Association Studies ◽

Genetic Correlations ◽

Genome Wide Association Studies ◽

Causal Association ◽

Study Objective ◽

Brain White Matter ◽

White Matter Microstructure ◽

Genetic Overlap ◽

Circadian Preference

AbstractStudy objectivePrevious neuroimaging studies have highlighted differences in white matter microstructure among individuals with different chronotypes, but it is unclear whether those differences are due to genetic or environmental factors.MethodsHere we leverage summary statistics from recent large-scale genome-wide association studies (GWAS) of chronotype and diffusion tensor imaging (DTI) measures to examine the genetic overlap and infer causal relationships between these traits.ResultsWe identified 29 significant pairwise genetic correlations, of which 13 also had evidence for a causal association. Negative genetic correlations were identified between chronotype and brain-wide mean, axial and radial diffusivities. When exploring individual tracts, ten negative genetic correlations were observed with mean diffusivities, 10 with axial diffusivities, 4 with radial diffusivities and 2 with mode of anisotropy. We found evidence for a possible causal association of chronotype with white matter microstructure in individual tracts including the posterior limb and retrolenticular part of the internal capsule; the genu and splenium of the corpus callosum and the posterior, superior and anterior regions of the corona radiata.ConclusionsOur results suggest that eveningness is associated with variation in tract-specific white matter microstructure and, for an evening person, increases in axial and / or radial diffusivities may influence a higher mean diffusivity. These findings add to our understanding of circadian preference and its relationship with the brain, providing new perspectives on the genetic neurological underpinnings of chronotype’s role in health and disease.Statement of SignificanceSleep is essential for a healthy brain function, particularly for neural organization and brain structure development. Individual chronotype differences have been associated with depression, schizophrenia, diabetes and obesity, among other conditions. Investigating the shared genetic aetiology between chronotype and white matter microstructure is essential to understand the neurological basis of individual variation in chronotype. In the present study, we show that tract-specific white matter microstructure is genetically correlated and causally associated with chronotype.

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Coupled Changes in Brain White Matter Microstructure and Fluid Intelligence in Later Life

Journal of Neuroscience ◽

10.1523/jneurosci.0862-15.2015 ◽

2015 ◽

Vol 35 (22) ◽

pp. 8672-8682 ◽

Cited By ~ 66

Author(s):

Stuart J. Ritchie ◽

Mark E. Bastin ◽

Elliot M. Tucker-Drob ◽

Susana Muñoz Maniega ◽

Laura E. Engelhardt ◽

...

Keyword(s):

White Matter ◽

Fluid Intelligence ◽

Later Life ◽

Brain White Matter ◽

White Matter Microstructure

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White Matter Microstructural Differences in Youth with Classical Congenital Adrenal Hyperplasia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab520 ◽

2021 ◽

Author(s):

Devyn L Cotter ◽

Anisa Azad ◽

Ryan P Cabeen ◽

Mimi S Kim ◽

Mitchell E Geffner ◽

...

Keyword(s):

White Matter ◽

Congenital Adrenal Hyperplasia ◽

Stria Terminalis ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Brain White Matter ◽

White Matter Microstructure ◽

Subcortical Regions ◽

21 Hydroxylase Deficiency ◽

Microstructural Integrity

Abstract Context Gray matter morphology in the prefrontal cortex and subcortical regions, including the hippocampus and amygdala, are affected in youth with classical congenital adrenal hyperplasia (CAH). It remains unclear if white matter connecting these aforementioned brain regions is compromised in youth with CAH. Objective To examine brain white matter microstructure in youth with CAH compared to controls. Design A cross-sectional sample of 23 youths with CAH due to 21-hydroxylase deficiency (12.9±3.5 year; 61% female) and 33 healthy controls (13.1±2.8 year; 61% female) with 3T multi-shell diffusion-weighted magnetic resonance brain scans. Main Outcome Measures Complementary modeling approaches, including diffusion tensor imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI), to examine in vivo white matter microstructure in six white matter tracts that innervate the prefrontal and subcortical regions. Results DTI showed CAH youth had lower fractional anisotropy in both the fornix and stria terminalis, and higher mean diffusivity in the fornix compared to controls. NODDI modeling revealed that CAH youth have a significantly higher orientation dispersion index in the stria terminalis compared to controls. Decreases in white matter microstructural integrity were associated with smaller hippocampal and amygdala volumes in CAH youth. Conclusions These patterns of microstructure reflect less restricted water diffusion likely due to less coherency in oriented microstructure. These results suggest that white matter microstructural integrity in the fornix and stria terminalis is compromised and may be an additional related brain phenotype alongside affected hippocampus and amygdala neurocircuitry in individuals with CAH.

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Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa134 ◽

2020 ◽

Author(s):

Maria A Di Biase ◽

Andrew Zalesky ◽

Suheyla Cetin-Karayumak ◽

Yogesh Rathi ◽

Jinglei Lv ◽

...

Keyword(s):

White Matter ◽

Large Scale ◽

Interleukin 2 ◽

Free Water ◽

Markers Of Inflammation ◽

Brain White Matter ◽

Inflammatory Processes ◽

Weighted Magnetic Resonance Imaging

Abstract Introduction Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. Methods All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. Results Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = −3.56, P = .0004) and IL-12(p70) (t = −2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P < .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. Conclusions We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.

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Direct and Indirect Associations of Widespread Individual Differences in Brain White Matter Microstructure with Executive Functioning and General and Specific Dimensions of Psychopathology in Children

Biological Psychiatry Cognitive Neuroscience and Neuroimaging ◽

10.1016/j.bpsc.2020.11.007 ◽

2020 ◽

Author(s):

Carlos Cardenas-Iniguez ◽

Tyler M. Moore ◽

Antonia N. Kaczkurkin ◽

Francisco A.C. Meyer ◽

Theodore D. Satterthwaite ◽

...

Keyword(s):

Individual Differences ◽

White Matter ◽

Executive Functioning ◽

Brain White Matter ◽

White Matter Microstructure

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Aberrant White Matter Networks Mediate Cognitive Impairment in Patients with Silent Lacunar Infarcts in Basal Ganglia Territory

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.67 ◽

2015 ◽

Vol 35 (9) ◽

pp. 1426-1434 ◽

Cited By ~ 9

Author(s):

Jinfu Tang ◽

Suyu Zhong ◽

Yaojing Chen ◽

Kewei Chen ◽

Junying Zhang ◽

...

Keyword(s):

White Matter ◽

Basal Ganglia ◽

Cognitive Deficits ◽

Large Scale ◽

Diffusion Tensor ◽

Brain Regions ◽

Lacunar Infarcts ◽

Healthy Elderly ◽

Brain White Matter ◽

Diffusion Tensor Imaging Tractography

Silent lacunar infarcts, which are present in over 20% of healthy elderly individuals, are associated with subtle deficits in cognitive functions. However, it remains largely unclear how these silent brain infarcts lead to cognitive deficits and even dementia. Here, we used diffusion tensor imaging tractography and graph theory to examine the topological organization of white matter networks in 27 patients with silent lacunar infarcts in the basal ganglia territory and 30 healthy controls. A whole-brain white matter network was constructed for each subject, where the graph nodes represented brain regions and the edges represented interregional white matter tracts. Compared with the controls, the patients exhibited a significant reduction in local efficiency and global efficiency. In addition, a total of eighteen brain regions showed significantly reduced nodal efficiency in patients. Intriguingly, nodal efficiency–behavior associations were significantly different between the two groups. The present findings provide new aspects into our understanding of silent infarcts that even small lesions in subcortical brain regions may affect large-scale cortical white matter network, as such may be the link between subcortical silent infarcts and the associated cognitive impairments. Our findings highlight the need for network-level neuroimaging assessment and more medical care for individuals with silent subcortical infarcts.

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