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Thursday
Mar302017

Schizophrenia and amyotrophic lateral sclerosis have more in common than we thought!

On the surface schizophrenia (SCZ) and amyotrophic lateral sclerosis (ALS) are quite different! SCZ is a chronic psychotic disorder that presents as a myriad of symptoms such as hallucinations and cognitive deficits, while ALS is a progressive neurodegenerative disorder that destroys motor neurons and downstream muscle movement. However, unexpected epidemiology links have emerged; higher than predicted rates of SCZ were discovered in relatives of ALS patients1 and polygenetic risk factors were identified in both patient populations2,3. Recently, McLaughlin et al. conducted a genome wide association study (GWAS) to compare polygenic risk factors between SCZ and ALS patients4. Association mapping of over 100,000 individuals identified a positive genetic correlation of 14%4. Interestingly, this correlation was specific to SCZ and was not found when comparing ALS to bipolar disorder, major depressive disorder, autism spectrum disorder, or Alzheimer’s disease. Supporting these results, authors found that SCZ polygenetic risk factors were significantly higher among ALS patients compared to healthy controls. Through this work novel ALS-associated genes were discovered, including genes with roles in axon connectivity and autoimmunity. The authors speculated that shared genetic risk factors between SCZ and ALS may converge on neural network dysregulation. The authors further suggested that therapeutic strategies beneficial for ALS may be beneficial for SCZ and vice versa.  

Given the shared genetic background and pathophysiological differences between SCZ and ALS, it is tempting to envision a role for epigenetic mechanisms in disease divergence. Moving forward it would be interesting to profile the occupancy of epigenetic enzymes on shared risk factor genes. It would also be interesting to compare in vivo epigenetic enzyme expression (for example with neuroepigenetic PET imaging!) in SCZ and ALS populations.

 

-TMG

1) Byrne, S. et al. Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: a population-based case–control cohort study of familial and sporadic amyotrophic lateral sclerosis. Ann. Neurol. 74, 699–708 (2013).

2) Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

3) van Rheenen, W. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat. Genet. 48, 1043–1048 (2016).

4) McLaughlin, R. et al. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat. Communications 8:14774 (2017).

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