A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment

Abstract

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 suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

Connecting gene regulatory relationships to neurobiological mechanisms of brain disorders

“…Developmental stages 5 and 6 both represent mid-gestation, the period during which upper layer neurons are generated and neuronal differentiation including axonogenesis and dendritic arborization takes place 22,23 . Therefore, this result collectively highlights mid-gestation as a critical window during neurodevelopment that may confer risk to multiple psychiatric disorders, consistent with recent results from cross-disorder GWAS 24,25 . On the contrary, neurodegenerative disorders showed a variety of distinct expression trajectories.…”

A large population-based investigation into the genetics of susceptibility to gastrointestinal infections and the link between gastrointestinal infections and mental illness

“…Cases were defined as having the relevant ICD code (for psychiatric diagnoses) or one of several codes in the gastrointestinal infections category (for gastrointestinal infections) as per the above criteria. There is very high comorbidity among the psychiatric cases in the iPSYCH cohort (Schork et al 2019b), and, for gastrointestinal infections, around 93% of the people who had gastrointestinal infections were also diagnosed with at least one other infection category from the previous section. It has been shown that individuals with one psychiatric diagnosis are more prone to getting another one, and this higher "comorbidity risk" can persist over time, as reported for a much larger Danish dataset (Plana-Ripoll et al 2019).…”

“…Given such compelling evidence for the connection between the gastrointestinal tract and psychiatric and neurodevelopmental disorders, which are known to be quite heritable (Schork et al 2019b), and given the importance of understanding the genetic basis of gastrointestinal infections to elucidate the disease mechanism on the path to better diagnosis and treatment, we sought to investigate gastrointestinal infections from both angles outlined above: the genetic architecture of susceptibility to gastrointestinal infections, and their links with psychiatric and neurodevelopmental disorders. To achieve this, we used a population-based Danish cohort of 65,534 individuals from the Integrative Psychiatric Research (iPSYCH) initiative (Pedersen et al 2017), chosen either for having at least one of the following psychiatric or neurodevelopmental disorders: ASD, ADHD, schizophrenia, bipolar disorder, depression and anorexia, or as part of a random population sample representative of the Danish population and not selected for mental disorders or infections.…”

Using genetics to examine a general liability to childhood psychopathology

“…For example, registry-based family and twin studies suggest that relatives of those with schizophrenia, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and depression are at elevated risk for a broad range of psychopathology -not just for the same disorder as the affected probands (Doherty and Owen 2014). Recent molecular genetic studies also provide evidence of common variant genetic overlaps between different psychiatric disorders; for example genetic correlations across schizophrenia, ADHD, ASD and mood disorders have been shown to range from 0.30 to 0.93 (Schork et al 2019). Current psychiatric nosology does not take into account these complex patterns of shared inheritance across phenotypes (Doherty and Owen 2014).…”