Biology subjects

Andreassen, O. A.

Publications and source records attributed to Andreassen, O. A..

24 records · Page 2Linked to original sources

bioRxiv2017

Polygenic hazard scores in preclinical Alzheimer’s disease

Identifying asymptomatic older individuals at elevated risk for developing Alzheimers disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE {varepsilon}4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high CERAD (amyloid) and Braak (tau) scores at autopsy, even among APOE {varepsilon}4 non-carriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimers neurodegeneration.

genetics↗

bioRxiv2017

Genetic networks of the oxytocin system in the human brain: A gene expression and large-scale fMRI meta-analysis study

Oxytocin is a neuropeptide involved in animal and human reproductive and social behaviour, with potential implications for a range of psychiatric disorders. However, the therapeutic potential of oxytocin in mental health care suggested by animal research has not been successfully translated into clinical practice, partly due to a poor understanding of the expression and distribution of the oxytocin signaling pathway in the human brain, and its complex interactions with other biological systems. Among the genes involved in the oxytocin signaling pathway, three genes have been frequently implicated in human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (central oxytocin secretion). We characterized the distribution of the OXT, OXTR, and CD38 mRNA across the brain, identified putative gene pathway interactions by comparing gene expression patterns across 29131 genes, and assessed associations between gene expression patterns and cognitive states via large-scale fMRI meta-analysis. In line with the animal literature, oxytocin pathway gene expression was enriched in central, temporal, and olfactory regions. Across the brain, there was high co-expression of the oxytocin pathway genes with both dopaminergic (DRD2) and muscarinic acetylcholine (CHRM4) genes, reflecting an anatomical basis for critical gene pathway interactions. Finally, fMRI meta-analysis revealed that oxytocin pathway maps correspond with motivation and emotion processing, demonstrating the value of probing gene expression maps to identify brain functional targets for future pharmacological trials.

neuroscience↗

bioRxiv2017

Estimating Degree Of Polygenicity, Causal Effect Size Variance, And Confounding Bias In GWAS Summary Statistics

Estimating the polygenicity (proportion of causally associated single nucleotide polymorphisms (SNPs)) and discoverability (effect size variance) of causal SNPs for human traits is currently of considerable interest. SNP-heritability is proportional to the product of these quantities. We present a basic model, using detailed linkage disequilibrium structure from an extensive reference panel, to estimate these quantities from genome-wide association studies (GWAS) summary statistics. We apply the model to diverse phenotypes and validate the implementation with simulations. We find model polygenicities ranging from [~=] 2 x 10-5 to [~=] 4 x 10-3, with discoverabilities similarly ranging over two orders of magnitude. A power analysis allows us to estimate the proportions of phenotypic variance explained additively by causal SNPs reaching genome-wide significance at current sample sizes, and map out sample sizes required to explain larger portions of additive SNP heritability. The model also allows for estimating residual inflation (or deflation from over-correcting of z-scores), and assessing compatibility of replication and discovery GWAS summary statistics. Author SummaryThere are ~10 million common variants in the genome of humans with European ancestry. For any particular phenotype a number of these variants will have some causal effect. It is of great interest to be able to quantify the number of these causal variants and the strength of their effect on the phenotype. Genome wide association studies (GWAS) produce very noisy summary statistics for the association between subsets of common variants and phenotypes. For any phenotype, these statistics collectively are difficult to interpret, but buried within them is the true landscape of causal effects. In this work, we posit a probability distribution for the causal effects, and assess its validity using simulations. Using a detailed reference panel of ~11 million common variants - among which only a small fraction are likely to be causal, but allowing for non-causal variants to show an association with the phenotype due to correlation with causal variants - we implement an exact procedure for estimating the number of causal variants and their mean strength of association with the phenotype. We find that, across different phenotypes, both these quantities - whose product allows for lower bound estimates of heritability - vary by orders of magnitude.

genomics↗

bioRxiv2017

Psychiatric Genomics: An Update and an Agenda

The Psychiatric Genomics Consortium (PGC) is the largest consortium in the history of psychiatry. In the past decade, this global effort has delivered a rapidly increasing flow of new knowledge about the fundamental basis of common psychiatric disorders, particularly given its dedication to rapid progress and open science. The PGC has recently commenced a program of research designed to deliver \"actionable\" findings - genomic results that (a) reveal the fundamental biology, (b) inform clinical practice, and (c) deliver new therapeutic targets. This is the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. The emerging findings suggest that we are entering into a phase of accelerated translation of genetic discoveries to impact psychiatric practice within a precision medicine framework.\n\nCollaboratorsPGC Coordinating Committee: Mark Daly, Michael Gill, John Kelsoe, Karestan Koenen, Douglas Levinson, Cathryn Lewis, Ben Neale, Danielle Posthuma, Jonathan Sebat, and Pamela Sklar.

genetics↗

bioRxiv2017

Human-specific methylated regions are enriched in schizophrenia

BackgroundOne explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants.\n\nResultsSchizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n=10,000) and bootstrapping (n=5,000) in INRICH (p<0.01). Some enrichment of association with height was observed at the gene level.\n\nConclusionsRegions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.

genetics↗

bioRxiv2016

The correlation between central and peripheral oxytocin concentrations: a systematic review and meta-analysis

There is growing interest in the role of the oxytocin system in social cognition and behavior. Peripheral oxytocin concentrations are regularly used to approximate central concentrations in psychiatric research. This methodological approach has obvious appeal given the invasiveness of cerebrospinal fluid collection. However, the validity of this approach and potential moderators of the association between central and peripheral levels are unclear. Thus, we conducted a pre-registered systematic search and meta-analysis of correlations between central and peripheral oxytocin concentrations. A search of databases yielded 17 eligible studies for effect size synthesis and moderator analysis, resulting in a total sample size of 516 participants and subjects. Overall, a positive association between central and peripheral oxytocin concentrations was revealed [r=0.29, 95% CI (0.15, 0.42), p<0.0001], along with a moderate-to-high level of heterogeneity across effect sizes [Q=88.14, p<0.0001], and no evidence of publication bias (p=0.45). This association was significantly moderated by experimental context [Qb(4), p=0.0016]. The strongest association was observed after intranasal oxytocin administration (r=0.67, p<.0001), a correlation that was significantly greater (p=.0002) than the equivalent association under baseline conditions (r=0.08, p=.31). These results support the use of peripheral levels of oxytocin as a marker of central levels, but only after exogenous oxytocin administration. Despite the popularity of using peripheral OT levels to approximate central levels during baseline conditions, this approach is not supported by the present results.

physiology↗