Researchers from Trinity College Dublin have shown for the first time that Motor Neurone Disease (MND) — also known as Amyotrophic Lateral Sclerosis (ALS) — and schizophrenia have a shared genetic origin, indicating that the causes of these diverse conditions are biologically linked. The work has just been published in the prestigious journal Nature Communications.
By analysing the genetic profiles of almost 13,000 MND cases and over 30,000 schizophrenia cases, the researchers have confirmed that many of the genes that are associated with these two very different conditions are the same. In fact, the research has shown an overlap of 14% in genetic susceptibility to the adult onset neuro-degeneration condition ALS/MND and the developmental neuropsychiatric disorder schizophrenia.
While overlaps between schizophrenia and other neuropsychiatric conditions including bipolar affective disorder and autism have been shown in the past, this is the first time that an overlap in genetic susceptibility between MND and psychiatric conditions has been shown. Dr Russell McLaughlin, Ussher Assistant Professor in Genome Analysis at Trinity College Dublin, and lead author of the paper said, “This study demonstrates the power of genetics in understanding the causes of diseases.” “While neurological and psychiatric conditions may have very different characteristics and clinical presentations, our work has shown that the biological pathways that lead to these diverse conditions have much in common.” Professor of Neurology in Trinity and Consultant Neurologist at the National Neuroscience Centre at Beaumont Hospital Dublin, Orla Hardiman, is the senior author and lead investigator on the project. Professor Hardiman said, “Our work over the years has shown us that MND is a much more complex disease than we originally thought. Our recent observations of links with psychiatric conditions in some families have made us think differently about how we should study MND. When combined with our clinical work and our studies using MRI and EEG, it becomes clear that MND is not just a disorder of individual nerve cells, but a disorder of the way these nerve cells talk to one another as part of a larger network.” She continued, “So instead of thinking of MND as a degeneration of one cell at a time, and looking for a ‘magic bullet’ treatment that works, we should think about MND in the same way that we think about schizophrenia, which is a problem of disruptions in connectivity between different regions of the brain, and we should look for drugs that help to stabilise the failing brain networks. “The other significant issue that this research brings up is that the divide between psychiatry and neurology is a false one.
We need to recognise that brain disease has many different manifestations, and the best way to develop new treatments is to understand the biology of what is happening. This will have major implications for how we classify diseases going forward, and in turn how we train our future doctors in both psychiatry and neurology. That in itself will have knock-on consequences for how society understands, approaches and treats people with psychiatric and neurological conditions.” The new research was prompted by earlier epidemiological studies by researchers at Trinity, led by Professor Hardiman.
These studies showed that people with MND were more likely than expected to have other family members with schizophrenia, and to have had another family member who had committed suicide. This was first noted as family histories were ascertained from people with MND in the National ALS Clinic and was subsequently investigated as part of case control studies in Ireland in which over 192 families with MND and 200 controls participated. Details of over 12,000 relatives were analysed and the rates of various neurological and psychiatric conditions calculated in family member of those with MND and controls. This work was subsequently published in the prestigious American journal the Annals of Neurology in 2013. This led the Trinity group to team up with European collaborators in MND including the University of Utrecht, Kings College London and members of the Project MinE and Psychiatric Genome Consortia to see if these epidemiological observations could be due to a genetic overlap between MND and schizophrenia. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative condition characterized by progressive loss of upper and lower motor neurons, leading to death from respiratory failure in 70% of patients within 3 years of symptom onset. Although ALS is often described as a primarily motor-system disease, extramotor involvement occurs in up to 50% of cases, with prominent executive and behavioural impairment, and behavioural variant frontotemporal dementia (FTD) in up to 14% of cases. A neuropsychiatric prodrome has been described in some people with ALS–FTD, and higher rates of schizophrenia and suicide have been reported in first and second degree relatives of those with ALS, particularly in kindreds associated with the C9orf72 hexanucleotide repeat expansion. These clinical and epidemiological observations suggest that ALS and schizophrenia may share heritability.
ALS and schizophrenia both have high heritability estimates (0.65 and 0.64, respectively); however the underlying genetic architectures of these heritable components appear to differ. Analysis of large genome-wide association study (GWAS) datasets has implicated over 100 independent risk loci for schizophrenia and estimated that a substantial proportion (23%) of the variance in underlying liability for schizophrenia is due to additive polygenic risk (many riskincreasing alleles of low individual effect combining to cause disease) conferred by common genetic variants6. This proportion, the single nucleotide polymorphism (SNP)-based heritability, is lower in ALS (8.2%), in which fewer than ten risk loci have been identified by GWAS7. Nevertheless, both diseases have polygenic components, but the extent to which they overlap has not been investigated.
The authors state, ‘Recently, methods to investigate overlap between polygenic traits using GWAS data have been developed. These methods assess either pleiotropy (identical genetic variants influencing both traits) or genetic correlation (identical alleles influencing both traits). Genetic correlation is related to heritability; for both measures, binary traits such as ALS and schizophrenia are typically modelled as extremes of an underlying continuous scale of liability to develop the trait. If two binary traits are genetically correlated, their liabilities covary, and this covariance is determined by both traits having identical risk alleles at overlapping risk loci. Studies of pleiotropy and genetic correlation have provided insights into the overlapping genetics of numerous traits and disorders, although none to date has implicated shared polygenic risk between neurodegenerative and neuropsychiatric disease. Here, we apply several techniques to identify and dissect the polygenic overlap between ALS and schizophrenia. We provide evidence for genetic correlation between the two disorders which is unlikely to be driven by diagnostic misclassification and we demonstrate a lack of polygenic overlap between ALS and other neuropsychiatric and neurological conditions, which could be due to limited power given the smaller cohort sizes for these studies.
‘There is evolving clinical, epidemiological and biological evidence for an association between ALS and psychotic illness, particularly schizophrenia. Genetic evidence of overlap to date has been based primarily on individual genes showing Mendelian inheritance, in particular the C9orf72 hexanucleotide repeat expansion, which is associated with ALS and FTD, and with psychosis in relatives of ALS patients. In this study, we have replicated SNP-based heritability estimates for ALS and schizophrenia using GWAS summary statistics, and have for the first time demonstrated significant overlap between the polygenic components of both diseases, estimating the genetic correlation to be 14.3%.
‘We have carefully controlled for confounding bias, including population stratification and shared control samples, and have shown through analysis of polygenic risk scores that the overlapping polygenic risk applies to SNPs that are modestly associated with both diseases. Given that our genetic correlation estimate relates to the polygenic components of ALS (hS2=8.2%) and schizophrenia (hS2=23%) and these estimates do not represent all heritability for both diseases, the accuracy of using schizophrenia-based PRS to predict ALS status in any patient is expected to be low (Nagelkerke’s R2=0.12% for PT=0.2), although statistically significant (P=8.4 x 10—7). Nevertheless, the positive genetic correlation of 14.3% indicates that the direction of effect of riskincreasing and protective alleles is consistently aligned between ALS and schizophrenia, suggesting convergent biological mechanisms between the two diseases.
‘Although phenotypically heterogeneous, both ALS and schizophrenia are clinically recognizable as syndromes. The common biological mechanisms underlying the association between the two conditions are not well understood, but are likely associated with disruption of cortical networks. Schizophrenia is a polygenic neurodevelopmental disorder characterized by a combination of positive symptoms (hallucinations and delusions), negative symptoms (diminished motivation, blunted affect, reduction in spontaneous speech and poor social functioning) and impairment over a broad range of cognitive abilities. ALS is a late onset complex genetic disease characterized by a predominantly motor phenotype with recently recognized extramotor features in 50% of patients, including cognitive impairment1. It has been suggested that the functional effects of risk genes in schizophrenia converge by modulating synaptic plasticity, and influencing the development and stabilization of cortical microcircuitry. In this context, our identification of CNTN6 (contactin 6, also known as NB-3, a neural adhesion protein important in axon development) as a novel pleiotropy-informed ALS-associated locus supports neural network dysregulation as a potential convergent mechanism of disease in ALS and schizophrenia.’
The Trinity group, along with their partners in the University of Utrecht, will continue to study the links between MND and psychiatric conditions using modern genetics, epidemiology and neuroimaging, and in this way will develop new and more effective treatments that are based on stabilizing disrupted brain networks.