Biology subjects

Dalvie, S.

Publications and source records attributed to Dalvie, S..

3 recordsLinked to original sources

bioRxiv2018

Variably methylated regions in the newborn epigenome: environmental, genetic and combined influences

BackgroundEpigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. We examined the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs), defined as consecutive CpGs showing the highest variability of DNAm in 4 independent cohorts (PREDO, DCHS, UCI, MoBa, N=2,934).\n\nResultsWe used Akaikes information criterion to test which factors best explained variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E) including maternal demographic, psychosocial and metabolism related phenotypes, genotypes in cis (G), or their additive (G+E) or interaction (GxE) effects. G+E and GxE models consistently best explained variability in DNAm of VMRs across the cohorts, with G explaining the remaining sites best. VMRs best explained by G, GxE or G+E, as well as their associated functional genetic variants (predicted using deep learning algorithms), were located in distinct genomic regions, with different enrichments for transcription and enhancer marks. Genetic variants of not only G and G+E models, but also of variants in GxE models were significantly enriched in genome wide association studies (GWAS) for complex disorders.\n\nConclusionGenetic and environmental factors in combination best explain DNAm at VMRs. The CpGs best explained by G, G+E or GxE are functionally distinct. The enrichment of GxE variants in GWAS for complex disorders supports their importance for disease risk.

genetics↗

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

Concordance Of Genetic Variation That Increases Risk For Tourette Syndrome And That Influences Its Underlying Neurocircuitry

BACKGROUNDThere have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variations that increase risk for TS - and its main symptom dimensions - influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS.\n\nMETHODSWe obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4,644 cases and 8,695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP Effect Concordance Analysis (SECA) was used to examine genetic pleiotropy - the same SNP affecting two traits - and concordance - the agreement in SNP effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage Disequilibrium Score Regression (LDSR) was used as validation of SECA.\n\nRESULTSSECA revealed significant pleiotropy between TS and putaminal (p=2x10-4) and caudal (p=4x10-4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p=1x10-3). LDSR lent additional support for the association between TS and thalamic volume (p=5.85x10-2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamic volume (p=1x10-3), as well as concordance between symmetry behaviour and greater putaminal volume (p=7x10-4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p<8x10-7) when conditioning on intracranial (rs2708146, q=0.046; and rs72853320, q=0.035 and hippocampal (rs1922786, q=0.001 volumes respectively.\n\nCONCLUSIONThese data indicate concordance for genetic variations involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

genomics↗