Enhancer locus in ch14q23.1 modulates brain asymmetric temporal regions involved in language processing

AbstractIdentifying the genes that contribute to the variability in brain regions involved in language processing may shed light on the evolution of brain structures essential to the emergence of language in Homo sapiens. The superior temporal asymmetrical pit (STAP), which is not observed in chimpanzees, represents an ideal phenotype to investigate the genetic variations that support human communication. The left STAP depth was significantly associated with a predicted enhancer annotation located in the 14q23.1 locus, between DACT1 and KIAA0586, in the UK Biobank British discovery sample (N=16,515). This association was replicated in the IMAGEN cohort (N=1,726) and the UK Biobank non-British validation sample (N=2,161). This genomic region was also associated to a lesser extent with the right STAP depth and the formation of sulcal interruptions, plis de passage, in the bilateral STAP but not with other structural brain MRI phenotypes, highlighting its notable association with the superior temporal regions. Diffusion MRI emphasized an association with the fractional anisotropy of the left auditory fibers of the corpus callosum and with networks involved in linguistic processing in resting-state functional MRI. Overall, this evidence demonstrates a specific relationship between this locus and the establishment of the superior temporal regions that support human communication.

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Enhancer Locus in ch14q23.1 Modulates Brain Asymmetric Temporal Regions Involved in Language Processing

Cerebral Cortex ◽

10.1093/cercor/bhaa112 ◽

2020 ◽

Vol 30 (10) ◽

pp. 5322-5332

Author(s):

Yann Le Guen ◽

François Leroy ◽

Cathy Philippe ◽

Jean-François Mangin ◽

Ghislaine Dehaene-Lambertz ◽

...

Keyword(s):

Language Processing ◽

Homo Sapiens ◽

Brain Mri ◽

Brain Structures ◽

Brain Regions ◽

Genomic Region ◽

Uk Biobank ◽

Human Communication ◽

Discovery Sample ◽

The Uk

Abstract Identifying the genes that contribute to the variability in brain regions involved in language processing may shed light on the evolution of brain structures essential to the emergence of language in Homo sapiens. The superior temporal asymmetrical pit (STAP), which is not observed in chimpanzees, represents an ideal phenotype to investigate the genetic variations that support human communication. The left STAP depth was significantly associated with a predicted enhancer annotation located in the 14q23.1 locus, between DACT1 and KIAA0586, in the UK Biobank British discovery sample (N = 16 515). This association was replicated in the IMAGEN cohort (N = 1726) and the UK Biobank non-British validation sample (N = 2161). This genomic region was also associated to a lesser extent with the right STAP depth and the formation of sulcal interruptions, “plis de passage,” in the bilateral STAP but not with other structural brain MRI phenotypes, highlighting its notable association with the superior temporal regions. Diffusion MRI emphasized an association with the fractional anisotropy of the left auditory fibers of the corpus callosum and with networks involved in linguistic processing in resting-state functional MRI. Overall, this evidence demonstrates a specific relationship between this locus and the establishment of the superior temporal regions that support human communication.

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Association of Visual Impairment with Brain Structure

10.1101/2021.01.09.21249189 ◽

2021 ◽

Author(s):

Zhuoting Zhu ◽

Wenyi Hu ◽

Huan Liao ◽

Danli Shi ◽

Zachary Tan ◽

...

Keyword(s):

Visual Impairment ◽

Brain Structures ◽

Brain Regions ◽

Uk Biobank ◽

Total Brain Volume ◽

Brain Volumes ◽

Total Brain ◽

Magnetic Resonance Imaging Mri ◽

The Uk ◽

Global Brain

AbstractObjectiveTo investigate the association of visual impairment (VI) with brain structures in the UK Biobank Study.MethodsThe UK Biobank Study is a large prospective study that recruited more than 500,000 participants aged 40-69 from 2006 to 2010 across the UK. Visual acuity (VA) of worse than 0.3 LogMAR units (Snellen 20/40) was defined as VI. Structural magnetic resonance imaging (MRI) data were obtained using a 3.0-T MRI imager. Volumetric measures of five global brain volumes (total brain volume, total grey matter, total white matter, cerebrospinal fluid (CSF), brain stem) and the volumes of seven specific brain region (thalamus, caudate nucleus, basal ganglia, pallidum, hippocampus, amygdala and nucleus accumbens) were included in the present analysis. Multivariable linear regression was used to investigate the association of VI with global and specific brain volumes.ResultsA total of 8976 participants free of neurological disorders at baseline assessment were included for the present analysis. The prevalence of VI was 0.02% (n=181). After adjusting for a range of cofounding factors, VI was significantly associated with decreased volumes of the total brain (β = -0.12, 95% confidence interval (CI) -0.23 to 0.00, P = 0.049), thalamus (β = -0.16, 95% CI -0.18 to -0.04, P = 0.010), caudatenucleus (β = -0.14, 95% CI -0.27 to 0.00, P = 0.046), pallidum (β = -0.15, 95% CI-0.27 to -0.02, P = 0.028) and amygdala (β = -0.18, 95% CI -0.31 to -0.04, P = 0.012).InterpretationWe found that VI is associated with a decrease in total brain volumes and the volumes of specific brain regions implicated in neurodegenerative diseases.

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Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-201080 ◽

2021 ◽

pp. 1-9

Author(s):

Janice L. Atkins ◽

Luke C. Pilling ◽

Christine J. Heales ◽

Sharon Savage ◽

Chia-Ling Kuo ◽

...

Keyword(s):

Iron Reduction ◽

Brain Mri ◽

European Ancestry ◽

Uk Biobank ◽

Brain Iron ◽

Mri Features ◽

Incident Dementia ◽

Hfe Mutations ◽

The Uk

Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2 * measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2 * measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.

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Genetic overlap between Alzheimer’s disease and depression mapped onto the brain

10.1101/2021.01.23.21250016 ◽

2021 ◽

Author(s):

Jennifer Monereo Sánchez ◽

Miranda T. Schram ◽

Oleksandr Frei ◽

Kevin O’Connell ◽

Alexey A. Shadrin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genome Wide Association Study ◽

Brain Mri ◽

Genetic Correlations ◽

Gaussian Mixture ◽

Brain Morphology ◽

Uk Biobank ◽

Genetic Overlap ◽

The Uk

ABSTRACTBackgroundAlzheimer’s disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterizing their genetic overlap may provide etiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects.MethodsWe applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD (n=79,145) and depression (n=450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (mean age 57.21 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data.ResultsMiXer estimated 98 causal genetic variants overlapping between the two disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD (B=-0.002, p=9.1×10−4) and depression (B=0.007, p=3.2×10−9) in the UK Biobank. This SNP was also associated with several regions of the corpus callosum volume anterior (B>0.024, p<8.6×10−4), third ventricle volume ventricle (B=-0.025, p=5.0×10−6), and inferior temporal gyrus surface area (B=0.017, p=5.3×10−4).DiscussionOur results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.

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Altered Cortical Brain Structure and Increased Risk for Disease Seen Decades After Perinatal Exposure to Maternal Smoking: A Study of 9000 Adults in the UK Biobank

Cerebral Cortex ◽

10.1093/cercor/bhz060 ◽

2019 ◽

Vol 29 (12) ◽

pp. 5217-5233 ◽

Cited By ~ 4

Author(s):

Lauren E Salminen ◽

Rand R Wilcox ◽

Alyssa H Zhu ◽

Brandalyn C Riedel ◽

Christopher R K Ching ◽

...

Keyword(s):

Brain Structure ◽

Brain Mri ◽

Population Based ◽

Smoke Exposure ◽

Sensitivity Analyses ◽

Uk Biobank ◽

Increased Risk ◽

Increase Risk ◽

Sensory Cortices ◽

The Uk

Abstract Secondhand smoke exposure is a major public health risk that is especially harmful to the developing brain, but it is unclear if early exposure affects brain structure during middle age and older adulthood. Here we analyzed brain MRI data from the UK Biobank in a population-based sample of individuals (ages 44–80) who were exposed (n = 2510) or unexposed (n = 6079) to smoking around birth. We used robust statistical models, including quantile regressions, to test the effect of perinatal smoke exposure (PSE) on cortical surface area (SA), thickness, and subcortical volumes. We hypothesized that PSE would be associated with cortical disruption in primary sensory areas compared to unexposed (PSE−) adults. After adjusting for multiple comparisons, SA was significantly lower in the pericalcarine (PCAL), inferior parietal (IPL), and regions of the temporal and frontal cortex of PSE+ adults; these abnormalities were associated with increased risk for several diseases, including circulatory and endocrine conditions. Sensitivity analyses conducted in a hold-out group of healthy participants (exposed, n = 109, unexposed, n = 315) replicated the effect of PSE on SA in the PCAL and IPL. Collectively our results show a negative, long term effect of PSE on sensory cortices that may increase risk for disease later in life.

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Adapting the UK Biobank brain imaging protocol and analysis pipeline for the C-MORE multi-organ study of COVID-19 survivors

10.1101/2021.05.19.21257316 ◽

2021 ◽

Author(s):

Ludovica Griffanti ◽

Betty Raman ◽

Fidel Alfaro-Almagro ◽

Nicola Filippini ◽

Mark Philip Cassar ◽

...

Keyword(s):

White Matter ◽

Brain Mri ◽

Mean Diffusivity ◽

Brain Anatomy ◽

Uk Biobank ◽

Analysis Pipeline ◽

Imaging Protocol ◽

Diffusion Weighted Images ◽

Radiology Reports ◽

The Uk

SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study. The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 minutes. The automated imaging pipeline derives 1575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, these quantitative measures were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed that recovered COVID-19 patients had a decrease in frontal grey matter volumes, an increased burden of white matter hyperintensities, and reduced mean diffusivity in the total and normal appearing white matter in the posterior thalamic radiation and sagittal stratum, relative to controls. These differences were generally more prominent in patients who received organ support. Increased T2* in the thalamus was also observed in recovered COVID-19 patients, with a more prominent increase for non-critical patients. This initial evidence of brain changes in COVID-19 survivors prompts the need for further investigations. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in large-scale studies. The pipeline is widely applicable and will contribute to new analyses to hopefully clarify the medium to long-term effects of COVID-19.

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Identifying genetic variants associated with cerebellar volume in 33,265 individuals from the UK-Biobank

10.1101/2020.11.24.393249 ◽

2020 ◽

Author(s):

Tom Chambers ◽

Valentina Escott-Price ◽

Sophie Legge ◽

Emily Baker ◽

Krish D. Singh ◽

...

Keyword(s):

Association Studies ◽

Brain Structures ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Protein Coding ◽

Cerebellar Volume ◽

Genome Wide ◽

Subcortical Brain Structures ◽

The Uk

AbstractThere is expanding interest in researching the cerebellum given accumulating evidence of its important contributions to cognitive and emotional functions, in addition to more established sensorimotor roles. While large genome-wide association studies (GWAS) have shed light on the common allele architecture of cortical and subcortical brain structures, the cerebellum remains under investigated. We conducted a meta-GWAS of cerebellar volume in 33,265 UK-Biobank European participants. Results show cerebellar volume to be moderately heritable (h2SNP=50.6%). We identified 33 independent genome-wide associated SNPs with total cerebellar volume, with 6 of these SNPs mapped to protein-coding genes and 5 more shown to alter cerebellar gene expression. We highlight 21 unique candidate genes for follow-up analysis. Cerebellar volume showed significant genetic correlation with brainstem, pallidum and thalamus volumes, but no significant correlations with neuropsychiatric phenotypes. Our results provide important new knowledge of the genetic architecture of cerebellar volume and its relationship with other brain phenotypes.

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Biological and clinical insights from genetics of insomnia symptoms

10.1101/257956 ◽

2018 ◽

Cited By ~ 4

Author(s):

Jacqueline M Lane ◽

Samuel Jones ◽

Hassan S Dashti ◽

Andrew R Wood ◽

Krishna Aragam ◽

...

Keyword(s):

Muscle Development ◽

Reproductive Traits ◽

Well Being ◽

Brain Regions ◽

Causal Link ◽

Subjective Well Being ◽

Uk Biobank ◽

The Uk ◽

Genomic Regions ◽

Insomnia Symptoms

ABSTRACTInsomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n=453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in Partners Biobank (n=2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis, phototransduction and muscle development pathways and of genes expressed in multiple brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being.One Sentence SummaryWe identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.

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Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders

Scientific Reports ◽

10.1038/s41598-020-76518-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Arinbjörn Kolbeinsson ◽

Sarah Filippi ◽

Yannis Panagakis ◽

Paul M. Matthews ◽

Paul Elliott ◽

...

Keyword(s):

Disease Risk ◽

Brain Mri ◽

Insular Cortex ◽

Later Life ◽

Brain Regions ◽

Type I ◽

Brain Ageing ◽

Mri Scans ◽

The Uk ◽

Systemic Health

AbstractBrain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict “healthy” brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular cortex. We then applied this model to data from an independent group of people not stratified for health. A phenome-wide association analysis of over 1,410 traits in the UK Biobank with differences between the predicted and chronological ages for the second group identified significant associations with over 40 traits including diseases (e.g., type I and type II diabetes), disease risk factors (e.g., increased diastolic blood pressure and body mass index), and poorer cognitive function. These observations highlight relationships between brain and systemic health and have implications for understanding contributions of the latter to late life dementia risk.

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Adapting the UK Biobank Brain Imaging Protocol and Analysis Pipeline for the C-MORE Multi-Organ Study of COVID-19 Survivors

Frontiers in Neurology ◽

10.3389/fneur.2021.753284 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ludovica Griffanti ◽

Betty Raman ◽

Fidel Alfaro-Almagro ◽

Nicola Filippini ◽

Mark Philip Cassar ◽

...

Keyword(s):

Large Scale ◽

Small Vessel Disease ◽

Brain Mri ◽

Brain Anatomy ◽

Uk Biobank ◽

Analysis Pipeline ◽

Imaging Protocol ◽

Diffusion Weighted Images ◽

Radiology Reports ◽

The Uk

SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the possible effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study. The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 min. The automated imaging pipeline derives 1,575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, IDPs related to atrophy, small vessel disease and olfactory bulbs were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed some group differences between recovered COVID-19 patients and controls, across severity groups, but not across anosmia groups. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in other large-scale studies. The protocol, pipeline code and data are openly available and will further contribute to the understanding of the medium to long-term effects of COVID-19.

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