20 Oct 2017

ALS used to be thought of as a disease purely of the motor system, but more recently scientists have uncovered ties with frontotemporal dementia, and even certain neuropsychiatric diseases. Now, scientists led by Orla Hardiman, Beaumont Hospital, Dublin, have tied ALS to a longer list of neuropsychiatric disorders. They reported in the October 16 JAMA Neurology that relatives of ALS patients were more likely than those of controls to have obsessive-compulsive disorder (OCD), autism, or alcoholism. The finding suggests that genes causing ALS can lead to different phenotypes in members of the same family.

Daniela Galimberti, University of Milan, who was not involved in the study, said that the data suggest a common mechanism between these diseases, but added that there is not yet an explanation.

“Our group has analyzed mainly psychoses, such as hallucinations and delusions," she said. "This is the first time other diseases have been considered, such as autism, alcoholism, or OCD.”

“This may in part explain the so-called ‘missing heritability’ of ALS,” wrote Hardiman. She referred to the gap between the estimated heritability of ALS from twin studies and the proportion of ALS for which the genetic reasons have been identified. “The missing heritability may in fact be manifesting as a different subphenotype or endophenotype in some kindreds,” she posits.

In a previous study, Hardiman’s group reported that family members of ALS patients developed more schizophrenia, psychotic illness, and suicidal behavior than those of controls (Byrne et al., 2013). Another found a 14 percent overlap in polygenic risk between ALS and schizophrenia (McLaughlin et al., 2017). In this study, first author Margaret O’Brien and colleagues wondered if the list of associated disorders extended even further.

To find out, the researchers recruited a cohort of 127 new ALS patients from the Irish ALS Register between January 2012 and January 2014 and asked them to complete a questionnaire about whether first-, second-, and third-degree relatives—parents, siblings, children, grandparents, uncles, and aunts, etc.—had been affected by schizophrenia, bipolar disorder, suicide, autism, obsessive-compulsive disorder, addiction, or alcoholism. The questionnaire only covered illness known before the onset of ALS in the patient, to a exclude a relative's stress-related response to their loved one being diagnosed with ALS. As controls, the researchers enrolled age- and sex-matched volunteers through the patients’ own or a nearby general practitioner. Most patients were genotyped for a hexanucleotide repeat expansion in C9ORF72, which has been associated with familial ALS and with neurologic and neuropsychiatric disorders, to see if diseases clustered only in families carrying the mutation.

In total, the ALS patients provided data on 2,116 relatives, while controls gave data on 2,139. Similar to their previous study, the researchers found that relatives of ALS patients were 3.4 times more likely than those of controls to develop schizophrenia or other psychotic illness, and 3.3 times more likely to commit suicide. Further, relatives of ALS patients had a 10-fold higher risk of autism, 5.6-fold risk for obsessive-compulsive disorder, and 1.5-fold risk of alcohol abuse. Of the 127 ALS patients, 77 reported at least one relative with a neuropsychiatric disorder, compared with 51 of the 132 controls. Of the study participants who reported three or more relatives with one of these disorders, 71 percent had ALS. “This points to disease heterogeneity within ALS,” wrote Hardiman. “ALS and neuropsychiatric conditions are biologically linked, but only within a subset of kindreds.” Those kindreds were not limited to C9ORF72 carriers, suggesting other genes or combinations thereof drive the association, the authors wrote.

Hardiman and colleagues are now asking how these seemingly different conditions might be biologically related. Disruptions in neural network connectivity have been associated with all of them, implying that could be the common denominator, the authors suggested (Li et al., 2015; Wang et al., 2017; Turner et al., 2015). Hardiman argued for investing in noninvasive markers of human ALS at the neural network level, as animals inadequately model connectivity in the human brain.

Riluzole, which is approved for treatment of ALS and has shown promise in both schizophrenia and OCD, also suggests a common mechanism among these disorders, wrote James Wymer and colleagues at the University of Florida, Gainesville, in an accompanying editorial. “Together, these data are very suggestive of an association between these diseases and may offer insight into new therapeutic options,” they wrote. “Further study is needed before we can conclude that there is any definitive association between them,” they added.

The authors acknowledged that survey responses can yield incomplete data. They are now working to fully characterize neuropsychiatric traits and genomic parameters in first- and second-degree relatives within ALS families.—Gwyneth Dickey Zakaib

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References

Paper Citations

1. Byrne S, Heverin M, Elamin M, Bede P, Lynch C, Kenna K, Maclaughlin R, Walsh C, Al Chalabi A, Hardiman O. 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. 2013 Jul 9; PubMed.
2. McLaughlin RL, Schijven D, van Rheenen W, van Eijk KR, O'Brien M, Kahn RS, Ophoff RA, Goris A, Bradley DG, Al-Chalabi A, van den Berg LH, Luykx JJ, Hardiman O, Veldink JH, Project MinE GWAS Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat Commun. 2017 Mar 21;8:14774. PubMed.
3. Li M, Deng W, He Z, Wang Q, Huang C, Jiang L, Gong Q, Ziedonis DM, King JA, Ma X, Zhang N, Li T. A splitting brain: Imbalanced neural networks in schizophrenia. Psychiatry Res. 2015 May 30;232(2):145-53. Epub 2015 Mar 11 PubMed.
4. Wang Y, Wang J, Jia Y, Zhong S, Niu M, Sun Y, Qi Z, Zhao L, Huang L, Huang R. Shared and Specific Intrinsic Functional Connectivity Patterns in Unmedicated Bipolar Disorder and Major Depressive Disorder. Sci Rep. 2017 Jun 15;7(1):3570. PubMed.
5. Turner MR, Verstraete E. What does imaging reveal about the pathology of amyotrophic lateral sclerosis?. Curr Neurol Neurosci Rep. 2015 Jul;15(7):45. PubMed.

Further Reading

Papers

1. Mioshi E, Roberts R, Hornberger M. Neuropsychiatric symptoms and survival in amyotrophic lateral sclerosis: a missing link?. Neurodegener Dis Manag. 2015;5(2):89-91. PubMed.
2. Mioshi E, Caga J, Lillo P, Hsieh S, Ramsey E, Devenney E, Hornberger M, Hodges JR, Kiernan MC. Neuropsychiatric changes precede classic motor symptoms in ALS and do not affect survival. Neurology. 2014 Jan 14;82(2):149-55. Epub 2013 Dec 11 PubMed.

News

1. Confirmed: ALS Attacks Cognition and Behavior 29 Jan 2016
2. ALS/FTD Genes Reveal Pathways to Pathology 24 Jun 2017
3. New Gene Strengthens Link Between ALS and FTD 22 Apr 2016
4. Twin Study Suggests Environment Modifies Genetic Risk for ALS 19 Sep 2014