In a recent study on the medRxiv* preprint server, researchers compared the shared genetic risk and biological foundations of neurological and mental illnesses using roughly one million cases from genome-wide association studies (GWAS).
Study: Impact of metagenomic next-generation sequencing of plasma cell-free DNA testing in the management of patients with suspected infectious diseases. Image Credit: r.classen/Shutterstock.com
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
Psychiatric and neurological diseases are the leading causes of morbidity and mortality globally. Despite their shared neural origin, they have distinct underlying pathogenic entities and are classified separately in the International Classification of Diseases (ICD). However, the degree to which they share an etiological basis and genetic influences is unclear.
Psychiatric disorders have a neurobiological basis, with in vivo investigations showing systematic brain abnormalities across various disorders.
Treatment modalities targeting neurobiological mechanisms are effective for many psychiatric disorders, including electroconvulsive therapy, transcranial magnetic stimulation, and psychopharmacological agents.
Clinical features of both disorders include debilitating symptoms, movement abnormalities, and cognitive impairment.
About the study
In the present study, researchers analyzed GWAS data using complementary statistical and computational tools to assess genomic overlap between neurological and psychiatric diseases and biologically interpret the genetic data to explore if the existing clinical divide between neurological and psychiatric disorders is visible at the genetic level.
The team curated summary statistics of genome-wide association studies to analyze data for ten psychiatric and ten neurological diseases. Psychiatric diseases included anorexia nervosa (AN), attention-deficit hyperactivity disorder (ADHD), anxiety disorders (ANX), autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), Tourette Syndrome (TS), post-traumatic stress disorder (PTSD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ).
Neurological disorders included Alzheimer's disease (ALZ), essential tremor (ET), amyotrophic lateral sclerosis (ALS), migraine (MIG), Lewy body dementia (LBD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and epilepsy of the genetic generalized (GGE) and focal types (FE).
In addition, the team included genome-wide association studies' information on brain-associated traits [cortical thickness (CRT-TH) and surface area (CRT-SA), general cognitive ability (COG), four somatic-type diseases [coronary artery disease (CAD), chronic kidney disease (CKD), diabetes mellitus type 2 (T2D), and inflammatory bowel disease (IBD)], and height for comparison.
The genome-wide association studies included only individuals of European ancestry individuals. After data pre-processing and harmonization, systematic biological interrogation and cross-disorder analyses were performed.
The genomic architectural characteristics discriminating each phenotype and the genetically overlapping statistically significant genes and loci were determined.
Global genomic correlation patterns across disease phenotypes were analyzed, and genomic overlapping beyond correlations was estimated.
Differentially involved biological cells and tissues across the genome-wide association studies were compared using ribonucleic acid (RNA) sequencing information provided by the Genotype-Tissue Expression (GTEx) project team, single-cell ribonucleic acid sequencing data from the human brain, and predetermined gene ontology (GO) datasets implemented in functional mapping and annotation of GWAS (FUMA).
Results
The findings revealed widespread genetic overlap across the disorders, with varying degrees of genetic correlations, most of which were positive. Migraines, essential tremors, multiple sclerosis, and stroke were genetically associated with various psychiatric diseases.
The overlapping genomic components indicated that neurological and psychiatric disorders partly share molecular genetic mechanisms and key etiological aspects, contrasting their clinical distinctions with a more central role of neuronal biology implicated in psychiatric disorders.
Biological interrogation indicated heterogeneous biological processes related to neurological diseases, while psychiatric disorders consistently implicated neuronal biology.
Psychiatric disorders were more polygenic than neurological disorders, with pediatric-onset disorders having the highest single nucleotide polymorphism (SNP) heritability. The finding supported the hypothesis that multiple causal pathways may converge on the same mental illness while fewer causal pathways may underlie neurological disorders.
The estimated polygenicity for psychiatric diseases and COG was greater than that for neurological diseases, somatic disorders, cortical imaging evaluations, and height. Most polygenic phenotypes had low discoverability, indicative of a higher proportion of trait-affecting variants with smaller effect sizes.
The study found that 40 of 45 genetic correlations among psychiatric disorders and 12 of 45 correlations among neurological disorders reached significance.
The neurodegenerative disorders ALS, LBD, ALZ, and PD formed a cluster of correlated disorders, with ET, FE, and stroke positively correlated with several psychiatric disorders, particularly MDD, ADHD, ANX, and PTSD. The scientific investigation uncovered a variety of brain-related correlations associated with neurological illnesses.
Risk genes for Parkinson's disease were shown to be highly related to numerous neurobiological processes, including synaptic vesicles. They were specifically elevated in the substantia nigra, which is crucial to the pathogenesis of Parkinson's disease.
GGE risk genes were strongly connected with excitatory and gamma-aminobutyric acid (GABA)ergic neurons, consistent with hyperexcitability being the pathophysiological hallmark of epilepsy.
Risk genes for LBD were connected to lipid metabolism, SCZ, MDD, and ADHD were all elevated in brain tissue, and neurobiological procedures and types of neuronal cells were involved. CRT-TH and COG were the only comparisons with significantly elevated genes in brain cells.
Conclusion
The study findings showed genetic overlap between psychiatric and neurological disorders, revealing convergence of biological associations and contrasting historically defined distinctions.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Some genetic mutations may offer protection against developmental disorders