Publications

Abstract

Objective
The aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disorders
Methods
We first assessed the number of single nucleotide polymorphisms (SNPs) with genome-wide significance for human metabolism (NHGRI-EBI Catalog). These 516 SNPs (216 independent loci) were looked-up in genome-wide association studies for association with body mass index (BMI) and the mental traits/disorders educational attainment, neuroticism, schizophrenia, well-being, anxiety, depressive symptoms, major depressive disorder, autism-spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's disease, bipolar disorder, aggressive behavior, and internalizing problems. A strict significance threshold of p < 6.92 × 10−6 was based on the correction for 516 SNPs and all 14 phenotypes, a second less conservative threshold (p < 9.69 × 10−5) on the correction for the 516 SNPs only.
Results
19 SNPs located in nine independent loci revealed p-values < 6.92 × 10−6; the less strict criterion was met by 41 SNPs in 24 independent loci. BMI and schizophrenia showed the most pronounced genetic overlap with human metabolism with three loci each meeting the strict significance threshold. Overall, genetic variation associated with estimated glomerular filtration rate showed up frequently; single metabolite SNPs were associated with more than one phenotype. Replications in independent samples were obtained for BMI and educational attainment.
Conclusions
Approximately 5–10% of the regions involved in the regulation of blood/urine metabolite levels seem to also play a role in BMI and mental traits/disorders and related phenotypes. If validated in metabolomic studies of the respective phenotypes, the associated blood/urine metabolites may enable novel preventive and therapeutic strategies.

Abstract

Large-scale genome-wide association studies (GWAS) have implicated many low-penetrance loci in schizophrenia. However, its pathological mechanisms are poorly understood, which in turn hampers the development of novel pharmacological treatments. Pathway and gene set analyses carry the potential to generate hypotheses about disease mechanisms and have provided biological context to genome-wide data of schizophrenia. We aimed to examine which biological processes are likely candidates to underlie schizophrenia by integrating novel and powerful pathway analysis tools using data from the largest Psychiatric Genomics Consortium schizophrenia GWAS (N=79,845) and the most recent 2018 schizophrenia GWAS (N=105,318). By applying a primary unbiased analysis (Multi-marker Analysis of GenoMic Annotation; MAGMA) to weigh the role of biological processes from the Molecular Signatures Database (MSigDB), we identified enrichment of common variants in synaptic plasticity and neuron differentiation gene sets. We supported these findings using MAGMA, Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA) and Interval Enrichment Analysis (INRICH) on detailed synaptic signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and found enrichment in mainly the dopaminergic and cholinergic synapses. Moreover, shared genes involved in these neurotransmitter systems had a large contribution to the observed enrichment, protein products of top genes in these pathways showed more direct and indirect interactions than expected by chance, and expression profiles of these genes were largely similar among brain tissues. In conclusion, we provide strong and consistent genetics and protein-interaction informed evidence for the role of postsynaptic signaling processes in schizophrenia, opening avenues for future translational and psychopharmacological studies.

Abstract

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Abstract

Background Peripartum depression is a common cause of pregnancy- and postpartum-related morbidity. The production of corticotropin-releasing hormone (CRH) from the placenta alters the profile of hypothalamus–pituitary–adrenal axis hormones and may be associated with postpartum depression. The purpose of this study was to assess, in nondepressed pregnant women, the possible association between CRH levels in pregnancy and depressive symptoms postpartum. Methods A questionnaire containing demographic data and the Edinburgh Postnatal Depression Scale (EPDS) was filled in gestational weeks 17 and 32, and 6 week postpartum. Blood samples were collected in week 17 for assessment of CRH. A logistic regression model was constructed, using postpartum EPDS score as the dependent variable and log-transformed CRH levels as the independent variable. Confounding factors were included in the model. Subanalyses after exclusion of study subjects with preterm birth, newborns small for gestational age (SGA), and women on corticosteroids were performed. Results Five hundred thirty-five women without depressive symptoms during pregnancy were included. Logistic regression showed an association between high CRH levels in gestational week 17 and postpartum depressive symptoms, before and after controlling for several confounders (unadjusted OR = 1.11, 95% CI 1.01–1.22; adjusted OR = 1.13, 95% CI 1.02–1.26; per 0.1 unit increase in log CRH). Exclusion of women with preterm birth and newborns SGA as well as women who used inhalation corticosteroids during pregnancy did not alter the results. Conclusions This study suggests an association between high CRH levels in gestational week 17 and the development of postpartum depressive symptoms, among women without depressive symptoms during pregnancy.