Biology subjects

Andreassen, O. A.

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

83 records · Page 5Linked to original sources

bioRxiv2017

Heritable cognitive and psychopathology factors in youth are predicted by brain fronto-temporal white matter pathway

A healthy transition from adolescence to adulthood relies on a continuous individual adaptation to a dynamic environment. Here, we employed data driven multivariate approaches to derive both general cognitive and psychopathology factors as well as brain phenotypes in children and adolescents in the publicly available PNC sample. We identified a distinct brain white matter pattern which proved central for prediction of heritable cognition and psychopathology scores, highlighting the importance of fronto-temporal connections for intellectual and mental development.

neuroscience↗

bioRxiv2017

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

BackgroundThere is an urgent need for the early identification of nondemented individuals at the highest risk of progressing to Alzheimers disease (AD) dementia for early therapeutic interventions. Our goal was to evaluate whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo CSF or PET biomarkers of amyloid or tau pathology to prospectively predict cognitive decline and clinical progression to AD dementia in nondemented older individuals.\n\nMethodsWe evaluated 347 cognitive normal (CN) and 599 mild cognitively impaired (MCI) individuals. We first investigated whether PHS can predict CSF or PET amyloid and tau deposition. We evaluated differences in positive and negative predictive values of biomarker status, as a function of PHS risk. Next, we used linear mixed-effects (LME) to examine if PHS and biomarker status in conjunction, best predict longitudinal cognitive and clinical progression. Lastly, we used survival analysis to investigate whether a combination of PHS and biomarker positivity predicts progression to AD dementia better than using PHS or biomarker positivity alone.\n\nFindingsIn CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%. Similarly, for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. Beyond APOE, high PHS individuals with amyloid and tau pathology showed the fastest rate of longitudinal cognitive decline and time to AD dementia progression. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression.\n\nInterpretationAmong asymptomatic and mildly symptomatic older individuals, PHS considerably improves the predictive value of CSF or PET amyloid and tau biomarkers. Beyond APOE, PHS may be useful for risk stratification and cohort enrichment for MCI and preclinical AD therapeutic trials.

genetics↗

bioRxiv2017

Estimating inflation in GWAS summary statistics due to variance distortion from cryptic relatedness

Cryptic relatedness is inherently a feature of large genome-wide association studies (GWAS), and can give rise to considerable inflation in summary statistics for single nucleotide polymorphism (SNP) associations with phenotypes. It has proven difficult to disentangle these inflationary effects from true polygenic effects. Here we present results of a model that enables estimation of polygenicity, mean strength of association, and residual inflation in GWAS summary statistics. We show that there is substantial residual inflation in recent large GWAS of height and schizophrenia; correcting for this reduces the number of independent genome-wide significant loci from the reported values of 697 for height and 108 for schizophrenia to 368 and 61, respectively. In contrast, a larger GWAS of educational attainment shows no residual inflation. Additionally, we find that height has a relatively low polygenicity, with approximately 8k SNPs having causal association, more than an order of magnitude less than has been reported. The residual inflation in GWAS summary statistics can be corrected using the standard genomic control procedure with the estimated residual inflation factor.

genomics↗

bioRxiv2017

Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories

Cognitive and brain development are determined by dynamic interactions between genes and environment across the lifespan. Aside from marker-by-marker analyses of polymorphisms, biologically meaningful features of the whole-genome (derived from the combined effect of individual markers) have been postulated to inform on human phenotypes including cognitive traits and their underlying biological substrate.\n\nHere, estimates of inbreeding and genetic susceptibility for schizophrenia calculated from genome-wide data -runs of homozygosity (ROH) and schizophrenia polygenic risk score (PGRS)- are analyzed in relation to cognitive abilities (n=4183) and brain structure (n=516) in a general-population sample of European-ancestry participants aged 8-22, from the Philadelphia Neurodevelopmental Cohort.\n\nThe findings suggest that a higher ROH burden and higher schizophrenia PGRS are associated with higher intelligence. Cognition~ROH and cognition~PGRS associations obtained in this cohort may respectively evidence that assortative mating influences intelligence, and that individuals with high schizophrenia genetic risk who do not transition to disease status are cognitively resilient.\n\nNeuroanatomical data showed that the effects of schizophrenia PGRS on cognition could be modulated by brain structure, although larger imaging datasets are needed to accurately disentangle the underlying neural mechanisms linking IQ with both inbreeding and the genetic burden for schizophrenia.

neuroscience↗

bioRxiv2017

Immune-related genetic enrichment in frontotemporal dementia

BackgroundConverging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.\n\nMethods and findingsUsing large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) - and one or more immune-mediated diseases including Crohns disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA) region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci within LRRK2 (Leucine Rich Repeat Kinase 2), TBKBP1 (TANK-binding kinase 1 Binding Protein 1), and PGBD5 (PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types.\n\nConclusionsWe show considerable immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

genetics↗

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↗