Biology subjects

Pedersen, C. B.

Publications and source records attributed to Pedersen, C. B..

4 recordsLinked to original sources

bioRxiv2018

Spatial gene-by-environment mapping for schizophrenia reveals locale of upbringing effects beyond urban-rural differences

Identification of mechanisms underlying the incidence of psychiatric disorders has been hampered by the difficulty in discovering highly-predictive environmental risk factors. For example, prior efforts have failed to establish environmental effects predicting geospatial clustering of schizophrenia incidence beyond urban-rural differences. Here, we employ a novel statistical framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing (place of residence, ages 0-7 years) and its synergistic effects with genetic liabilities (polygenic risk for schizophrenia). We use this statistical framework to analyze unprecedented geolocation and genotyping data in a case-cohort study of n=24,028 subjects, drawn from the 1.47 million Danish persons born between 1981 and 2005. Using this framework we estimate the effects of upbringing locale (E) and gene-by-locale interactions (GxE). After controlling for potential confounding variables, upbringing at high-risk locales increases the risk for schizophrenia on average by 122%, while GxE modulates genetic risk for schizophrenia on average by 78%. Within the boundaries of Copenhagen (the largest and most densely populated city of Denmark) specific locales vary substantially in their E and GxE effects, with hazard ratios ranging from 0.26 to 9.26 for E and from 0.20 to 5.95 for GxE. This study provides insight into the degree of geospatial clustering of schizophrenia risk, and our novel analytic procedure provides a framework for decomposing variation in geospatial risk into G, E, and GxE components.

epidemiology↗

bioRxiv2017

A genome-wide association study for shared risk across major psychiatric disorders in a nation-wide birth cohort implicates fetal neurodevelopment as a key mediator

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here, we leverage the unique iPSYCH study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder SNP-heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during midgestation. This epoch is supported by partitioning cross-disorder SNP-heritability which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings indicate that dysregulation of genes that direct neurodevelopment by common genetic variants results in general liability for many later psychiatric outcomes.

genetics↗

bioRxiv2017

The iPSYCH2012 case-cohort sample: New directions for unravelling genetic and environmental architectures of severe mental disorders

The iPSYCH consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born 1981-2005 including 1,472,762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3,540), autism (N=16,146), ADHD (N=18,726), and affective disorder (N=26,380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30,000). Within the sample of 86,189 individuals, a total of 57,377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

genetics↗

bioRxiv2017

Discovery Of The First Genome-Wide Significant Risk Loci For ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of school-age children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no individual variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 ADHD cases and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, revealing new and important information on the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes, as well as around brain-expressed regulatory marks. These findings, based on clinical interviews and/or medical records are supported by additional analyses of a self-reported ADHD sample and a study of quantitative measures of ADHD symptoms in the population. Meta-analyzing these data with our primary scan yielded a total of 16 genome-wide significant loci. The results support the hypothesis that clinical diagnosis of ADHD is an extreme expression of one or more continuous heritable traits.

genetics↗