Conor V. Dolan

Bio: Conor V. Dolan is an academic researcher from VU University Amsterdam. The author has contributed to research in topics: Heritability & Twin study. The author has an hindex of 55, co-authored 244 publications receiving 12558 citations. Previous affiliations of Conor V. Dolan include VU University Medical Center & Public Health Research Institute.

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

A dynamical model of general intelligence: the positive manifold of intelligence by mutualism.

Abstract: Scores on cognitive tasks used in intelligence tests correlate positively with each other, that is, they display a positive manifold of correlations. The positive manifold is often explained by positing a dominant latent variable, the g factor, associated with a single quantitative cognitive or biological process or capacity. In this article, a new explanation of the positive manifold based on a dynamical model is proposed, in which reciprocal causation or mutualism plays a central role. It is shown that the positive manifold emerges purely by positive beneficial interactions between cognitive processes during development. A single underlying g factor plays no role in the model. The model offers explanations of important findings in intelligence research, such as the hierarchical factor structure of intelligence, the low predictability of intelligence from early childhood performance, the integration/differentiation effect, the increase in heritability of g, and the Jensen effect, and is consistent with current explanations of the Flynn effect.

A solution to dependency: using multilevel analysis to accommodate nested data

Abstract: In neuroscience, experimental designs in which multiple observations are collected from a single research object (for example, multiple neurons from one animal) are common: 53% of 314 reviewed papers from five renowned journals included this type of data These so-called 'nested designs' yield data that cannot be considered to be independent, and so violate the independency assumption of conventional statistical methods such as the t test Ignoring this dependency results in a probability of incorrectly concluding that an effect is statistically significant that is far higher (up to 80%) than the nominal α level (usually set at 5%) We discuss the factors affecting the type I error rate and the statistical power in nested data, methods that accommodate dependency between observations and ways to determine the optimal study design when data are nested Notably, optimization of experimental designs nearly always concerns collection of more truly independent observations, rather than more observations from one research object

Genetic and environmental influences interact with age and sex in shaping the human methylome

Abstract: The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.

Human biochemical genetics

Abstract: So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

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Integrative analysis of 111 reference human epigenomes

Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.