scholarly journals The genetic architecture of the human cerebral cortex

Science ◽  
2020 ◽  
Vol 367 (6484) ◽  
pp. eaay6690 ◽  
Author(s):  
Katrina L. Grasby ◽  
Neda Jahanshad ◽  
Jodie N. Painter ◽  
Lucía Colodro-Conde ◽  
Janita Bralten ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Surface Area ◽  
Meta Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Regulatory Elements ◽  
Total Surface Area ◽  
Imaging Data ◽  
Cortical Structure ◽  
A Genome ◽  
Significant Enrichment

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

scholarly journals The genetic architecture of the human cerebral cortex

2018 ◽  
Author(s):  
Katrina L. Grasby ◽  
Neda Jahanshad ◽  
Jodie N. Painter ◽  
Lucía Colodro-Conde ◽  
Janita Bralten ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Surface Area ◽  
Multiple Testing ◽  
Meta Analysis ◽  
Brain Mri ◽  
Regulatory Elements ◽  
Total Surface Area ◽  
Multiple Testing Correction ◽  
Cortical Structure ◽  
A Genome

The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci (P≤ 5 × 10−8); 199 survived multiple testing correction (P≤ 8.3 × 10−10; 187 surface area; 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression and ADHD.One Sentence SummaryCommon genetic variation is associated with inter-individual variation in the structure of the human cortex, both globally and within specific regions, and is shared with genetic risk factors for some neuropsychiatric disorders.

scholarly journals Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals

2021 ◽  
Vol 118 (47) ◽  
pp. e2113095118
Author(s):  
Zhiqiang Sha ◽  
Antonietta Pepe ◽  
Dick Schijven ◽  
Amaia Carrión-Castillo ◽  
James M. Roe ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Surface Area ◽  
Image Data ◽  
Hand Preference ◽  
Occipital Cortex ◽  
Imaging Data ◽  
Left Handedness ◽  
Genome Wide ◽  
Cortical Regions ◽  
Related Proteins

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7—mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

scholarly journals Cortical structure and the risk for Alzheimer’s disease: a bidirectional Mendelian randomization study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bang-Sheng Wu ◽  
Ya-Ru Zhang ◽  
Hong-Qi Li ◽  
Kevin Kuo ◽  
Shi-Dong Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Causal Relationship ◽  
Surface Area ◽  
Mendelian Randomization ◽  
Brain Area ◽  
Meta Analysis ◽  
European Ancestry ◽  
Cortical Structure ◽  
Temporal Pole

AbstractProgressive loss of neurons in a specific brain area is one of the manifestations of Alzheimer’s disease (AD). Much effort has been devoted to investigating brain atrophy and AD. However, the causal relationship between cortical structure and AD is not clear. We conducted a bidirectional two-sample Mendelian randomization analysis to investigate the causal relationship between cortical structure (surface area and thickness of the whole cortex and 34 cortical regions) and AD risk. Genetic variants used as instruments came from a large genome-wide association meta-analysis of cortical structure (33,992 participants of European ancestry) and AD (AD and AD-by-proxy, 71,880 cases, 383,378 controls). We found suggestive associations of the decreased surface area of the temporal pole (OR (95% CI): 0.95 (0.9, 0.997), p = 0.04), and decreased thickness of cuneus (OR (95% CI): 0.93 (0.89, 0.98), p = 0.006) with higher AD risk. We also found a suggestive association of vulnerability to AD with the decreased surface area of precentral (β (SE): –43.4 (21.3), p = 0.042) and isthmus cingulate (β (SE): –18.5 (7.3), p = 0.011). However, none of the Bonferroni-corrected p values of the causal relationship between cortical structure and AD met the threshold. We show suggestive evidence of an association of the atrophy of the temporal pole and cuneus with higher AD risk. In the other direction, there was a suggestive causal relationship between vulnerability to AD and the decreased surface area of the precentral and isthmus cingulate. Our findings shed light on the associations of cortical structure with the occurrence of AD.

scholarly journals IMPACT: Genomic annotation of cell-state-specific regulatory elements inferred from the epigenome of bound transcription factors

2018 ◽  
Author(s):  
Tiffany Amariuta ◽  
Yang Luo ◽  
Steven Gazal ◽  
Emma E. Davenport ◽  
Bryce van de Geijn ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Complex Trait ◽  
Cell Types ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Value Capture ◽  
Cell State ◽  
A Genome ◽  
Significant Enrichment

Despite significant progress in annotating the genome with experimental methods, much of the regulatory noncoding genome remains poorly defined. Here we assert that regulatory elements may be characterized by leveraging local epigenomic signatures at sites where specific transcription factors (TFs) are bound. To link these two identifying features, we introduce IMPACT, a genome annotation strategy which identifies regulatory elements defined by cell-state-specific TF binding profiles, learned from 515 chromatin and sequence annotations. We validate IMPACT using multiple compelling applications. First, IMPACT predicts TF motif binding with high accuracy (average AUC 0.92, s.e. 0.03; across 8 TFs), a significant improvement (all p<6.9e-15) over intersecting motifs with open chromatin (average AUC 0.66, s.e. 0.11). Second, an IMPACT annotation trained on RNA polymerase II is more enriched for peripheral blood cis-eQTL variation (N=3,754) than sequence based annotations, such as promoters and regions around the TSS, (permutation p<1e-3, 25% average increase in enrichment). Third, integration with rheumatoid arthritis (RA) summary statistics from European (N=38,242) and East Asian (N=22,515) populations revealed that the top 5% of CD4+ Treg IMPACT regulatory elements capture 85.7% (s.e. 19.4%) of RA h2 (p<1.6e-5) and that the top 9.8% of Treg IMPACT regulatory elements, consisting of all SNPs with a non-zero annotation value, capture 97.3% (s.e. 18.2%) of RA h2 (p<7.6e-7), the most comprehensive explanation for RA h2 to date. In comparison, the average RA h2 captured by compared CD4+ T histone marks is 42.3% and by CD4+ T specifically expressed gene sets is 36.4%. Finally, integration with RA fine-mapping data (N=27,345) revealed a significant enrichment (2.87, p<8.6e-3) of putatively causal variants across 20 RA associated loci in the top 1% of CD4+ Treg IMPACT regulatory regions. Overall, we find that IMPACT generalizes well to other cell types in identifying complex trait associated regulatory elements.

scholarly journals Personality and local brain structure: their shared genetic basis and reproducibility

2019 ◽  
Author(s):  
Sofie L. Valk ◽  
Felix Hoffstaedter ◽  
Julia A. Camilleri ◽  
Peter Kochunov ◽  
B.T. Thomas Yeo ◽  
...  
Keyword(s):  
Personality Traits ◽  
Surface Area ◽  
Brain Structure ◽  
Large Scale ◽  
Local Variation ◽  
Total Surface Area ◽  
Frontal Surface ◽  
Cortical Structure ◽  
Human Connectome Project ◽  
Local Brain

AbstractLocal variation in cortical architecture is highly heritable and distinct genes are associated with specific cortical regions. Total surface area has been shown to be genetically correlated with complex cognitive capacities, suggesting cortical brain structure is a viable endophenotype linking genes to behavior. However, to what extend local brain structure has a genetic association with cognitive and emotional functioning is incompletely understood. Here, we study the genetic correlation between personality traits and local cortical structure in a large-scale twin sample (Human Connectome Project, n=1106, 22-37y). We found a genetic overlap between personality traits and local cortical structure in 10 of 17 observed phenotypic associations in predominantly frontal cortices. To evaluate the robustness of observed personality-brain associations we studied two independent age-matched samples (GSP: n=926, age=19-35y, eNKI: n=210, age: 19-39y). We observed anecdotal to moderate evidence for a successful replication of the negative association between surface area in medial prefrontal cortex and Neuroticism in both samples. Quantitative functional decoding indicated this region is implicated in emotional and socio-cognitive functional processes. In sum, our observations suggest that associations between local brain structure and personality are, in part, under genetic control. However, associations are weak and only the relation between frontal surface area and Neuroticism was consistently observed across three independent samples of young adults.

scholarly journals Left-handedness and its genetic influences are associated with structural asymmetries mapped across the cerebral cortex in 31,864 individuals

2021 ◽  
Author(s):  
Zhiqiang Sha ◽  
Antonietta Pepe ◽  
Dick Schijven ◽  
Amaia Carrion Castillo ◽  
James M. Roe ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Surface Area ◽  
Image Data ◽  
Hand Preference ◽  
Occipital Cortex ◽  
Imaging Data ◽  
Left Handedness ◽  
Genome Wide ◽  
Cortical Regions ◽  
Related Proteins

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We re-sampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers and right-handers showed average differences of surface area asymmetry within fusiform, anterior insular, anterior-middle-cingulate and precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2 and NME7 - the latter is mutated in left-right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas non-heritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

scholarly journals Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Pinpin Long ◽  
Qiuhong Wang ◽  
Yizhi Zhang ◽  
Xiaoyan Zhu ◽  
Kuai Yu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Coronary Syndrome ◽  
Methylation Level ◽  
Meta Analysis ◽  
Regulation Of Gene Expression ◽  
Density Lipoprotein ◽  
Blood Leukocytes ◽  
Coronary Syndrome ◽  
A Genome ◽  
Increased Risk

Abstract Background Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear. Methods We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study. Results We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02–1.48; P = 0.03). Conclusions We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.

scholarly journals A genome-wide map of regulatory elements in zebrafish

Lab Animal ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 17-17
Author(s):  
Alexandra Le Bras
Keyword(s):  
Regulatory Elements ◽  
Genome Wide ◽  
A Genome
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