Biology subjects

Armstrong, N. J.

Publications and source records attributed to Armstrong, N. J..

5 recordsLinked to original sources

bioRxiv2018

The genetic architecture of the human cerebral cortex

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 x 10-8); 199 survived multiple testing correction (P [≤] 8.3 x 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, Parkinsons disease, insomnia, depression and ADHD.\n\nOne 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.

genetics↗

bioRxiv2018

Replication timing shapes the cancer epigenome and the nature of chromosomal rearrangements

HighlightsO_LIReplication timing alterations are conserved in cancers of different cell origins\nC_LIO_LILong-range epigenetic deregulation in cancer involves altered replication timing\nC_LIO_LICancer late-replicating loci are hypomethylated and acquire facultative heterochromatin\nC_LIO_LIReplication timing status potentiates cis and trans chromosomal rearrangements\nC_LI\n\nSummaryReplication timing is known to facilitate the establishment of epigenome, however, the intimate connection between DNA replication timing and changes to the genome and epigenome in cancer remain uncharted. Here, we perform Repli-Seq and integrated epigenome analysis and show that early-replicating loci are predisposed to hypermethylation and late-replicating loci to hypomethylation, enrichment of H3K27me3 and concomitant loss of H3K9me3. We find that altered replication timing domains correspond to long-range epigenetically deregulated regions in prostate cancer, and a subset of these domains are remarkably conserved across cancers from different tissue origins. Analyses of 214 prostate and 35 breast cancer genomes reveal that late-replicating DNA is prone to cis and early-replicating DNA to trans chromosomal rearrangements. We propose that differences in epigenetic deregulation related to spatial and temporal positioning between early and late replication potentiate the landscape of chromosomal rearrangements in cancer.

genomics↗

bioRxiv2017

Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.\n\nSignificance StatementLeft-right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population, and how biological factors such as age, sex and genetic variation affect these asymmetries. Here we describe by far the largest ever study of cerebral cortical brain asymmetry, based on data from 17,141 participants. We found a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an on-line resource that will serve future studies of human brain anatomy in health and disease.

neuroscience↗

bioRxiv2017

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

genetics↗

bioRxiv2017

An epigenome-wide association study of educational attainment (n = 10,767)

The epigenome has been shown to be influenced by biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption, and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here, we provide evidence on the associations between epigenetic modifications--in our case, CpG methylation--and educational attainment (EA), a biologically distal environmental factor that is arguably among of the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals. While we find that 9 CpG probes are significantly associated with EA, only two remain associated when we restrict the sample to never-smokers. These two are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, their effect sizes on EA are far smaller than the known associations between CpG probes and biologically proximal environmental factors. Two analyses that combine the effects of many probes--polygenic methylation score and epigenetic-clock analyses--both suggest small associations with EA. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

genetics↗