Schizophrenia, ALS Share Genetic Roots

Megan Brooks

March 31, 2017

Schizophrenia and amyotrophic lateral sclerosis (ALS) share a genetic origin, according to results of a genome-wide association study by an international group of researchers.

Investigators found "significant overlap" of about 14% between the polygenic components of both diseases, the researchers say.

Although previous studies have reported genetic links between schizophrenia and other neuropsychiatric conditions, including bipolar affective disorder and autism spectrum disorder, this study marks the first time that an overlap in genetic susceptibility between ALS and psychiatric conditions has been shown, they note.

The study was published online March 21 in Nature Communications.

Common Biological Pathways

"This study demonstrates the power of genetics in understanding the causes of diseases," lead author Russell McLaughlin, PhD, of Trinity College Dublin, in Ireland, said in a news release. "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," he added.

In an earlier study, the researchers observed "higher than expected" rates of schizophrenia in relatives of patients with ALS, suggesting an etiologic relationship between the two diseases.

In this latest study, they investigated genetic ties between ALS and schizophrenia using genome-wide association study data from more than 100,000 individuals.

Using linkage disequilibrium score regression, they estimated the genetic correlation between ALS and schizophrenia to be 14.3%, with schizophrenia polygenic risk scores accounting for up to 0.12% of the variance in ALS.

The current study supports "evolving clinical, epidemiological and biological evidence" for a genetic relationship between ALS and psychotic illness, particularly schizophrenia, the researchers note.

Therapeutic Implications

This "novel" observation, they add, underscores the "intriguing possibility that therapeutic strategies for each condition may be useful in the other, and our findings provide rationale to consider the biology of ALS and schizophrenia as related in future drug development studies."

In particular, the researchers note that a glutamate blocker used to treat ALS, riluzole (Rilutek, Teglutik), has shown efficacy as an adjunct to the antipsychotic drug risperidone (Risperdal, Janssen) in reducing the negative symptoms of schizophrenia.

"As both ALS and schizophrenia are heterogeneous conditions, further genomic, biological and clinical studies are likely to yield novel insights into the pathological processes for both diseases and will provide clinical substratification parameters that could drive novel drug development for both neurodegenerative and psychiatric conditions," the investigators conclude.

In the news release, senior author Prof Orla Hardiman, Trinity College Dublin, who is director of the National ALS Clinic and Irish ALS Research Group, noted that mounting evidence indicates that ALS/motor neurone disease [MND] is a "much more complex disease than we originally thought.

"So instead of thinking of ALS/MND as a degeneration of one cell at a time and looking for a 'magic bullet' treatment that works, we should think about ALS/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 stabilize the failing brain networks," said Dr Hardiman.

She added that the dividing line between psychiatry and neurology is a false one.

"We need to recognize that brain disease has many different manifestations, and the best way to develop new treatments is to understand the biology of what is happening," she said.

The study received support from a variety of noncommercial organizations. Several authors have disclosed financial relationships with various pharmaceutical companies. All are listed with the original article.

Nat Commun. Published online March 21, 2017. Full text

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