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expert reaction to study on air pollution, polygenic risk score and schizophrenia

Research, published in JAMA Network Open, reports that risk of developing schizophrenia may be heightened by childhood exposure to air pollution. 


Prof David Curtis, Retired Consultant Psychiatrist and Honorary Professor at UCL and QMUL, said:

“The main point of this study is to show that there is a correlation between childhood exposure to NO2 and subsequent risk of schizophrenia, and that this correlation is not due entirely to the fact that children at high genetic risk of schizophrenia tend to grow up in areas with high NO2. There is a recognised association between schizophrenia risk with urban dwelling and with socioeconomic deprivation. Although the authors have tried to control for these factors, it is not obvious that the observed association with NO2 reflects a direct causal effect of NO2, whether the NO2 level is an index of other air pollution or whether the association relates to other forms of deprivation which might themselves increase schizophrenia risk. So I don’t think that overall it adds very much to what we know about causal factors for schizophrenia.”

“Although the reported association is statistically significant because of the large numbers studied, we should bear in mind that the effect sizes are very small and so do not have any real implications at the level of individual risk.”


Prof Paul Bebbington, Emeritus Professor of Social and Community Psychiatry, University College London, said:

“Schizophrenia is a severe mental disorder characterised by unusual beliefs and experiences (delusions and hallucinations). It runs in families but is also related to past exposure to adverse circumstances and experiences. It is more common in people living in urban environments, an association that could be the result of a tendency of disorder-prone individuals to move to cities. It could also be due to the social stresses of urban living or to the effects of high levels of atmospheric pollution. The authors of this Danish study test out the hypothesis that the adverse effect of city living on the frequency of schizophrenia is related to increased atmospheric levels of nitrogen dioxide. They are able to investigate this because in Denmark there is virtually universal registration of individual members of the population from birth onward, including information on the various places they have lived in, and their contact with psychiatric services for mental disorders. There is also information on levels of atmospheric nitrogen dioxide that is extremely detailed both in terms of date and of location.

“One of the complicating issues affect a study of this nature is that people who suffer from schizophrenia may live in cities because one or more of their parents may have drifted there because of a genetic propensity to schizophrenia that they share with their offspring. This would introduce a risk that the apparent effect of city living was actually the result of this shared intergenerational propensity. The analysis in the current paper is therefore designed to control for this possibility, by controlling for familiarity as reflected in the polygenic risk score, basically a count of genetic factors associated with schizophrenia. In particular the authors investigated whether (1) childhood nitrogen dioxide exposure is correlated with the polygenic risk score for schizophrenia; (2) whether childhood nitrogen dioxide exposure and polygenic risk score for schizophrenia are in fact associated with schizophrenia; (3) whether the polygenic risk score changes the association between childhood nitrogen dioxide exposure and schizophrenia; and (4) whether the polygenic risk score and childhood nitrogen dioxide exposure interact in their effect on the emergence of schizophrenia.

“Individuals with a schizophrenia diagnosis as inpatient or outpatient or emergency department contact at a psychiatric hospital were ascertained through the Danish Psychiatric Central Research Register (ICD-10 code F20).

“The authors found a correlation between childhood nitrogen dioxide exposure and polygenic risk score for schizophrenia: both of these were associated with the development of schizophrenia. However, the two factors appeared to act more or less independently on the emergence of schizophrenia. The implication is that nitrogen dioxide pollution may, on its own, increase the risk of schizophrenia. This raises the question of how this could work. Possibilities include inflammation of the tissue of the nervous system by nitrogen dioxide, untoward proliferation of microglia (cells that normally maintain normal brain function), accumulation of potentially damaging proteins, and disruption of the blood-brain barrier. These are all speculative.

“This paper uses unique, detailed and extensive databases to provide an answer to the question raised by the authors in relation to a possible role of pollution. The analyses were sophisticated and persuasive, even if the findings raise many questions. Nevertheless, the idea that pollution may have a direct physical effect on the later emergence of schizophrenia remains a distinct possibility for further investigation.

“There was one peculiarity about the sample: The authors took a random sample of 30,000 individuals from a potential study population of nearly 1 ½ million. Around 23,000 eventually provided the basis for the analysis. 3531 developed schizophrenia, i.e. 15%. This is impossibly high unless there was some stratification with under-sampling of the non-affected group. However, the authors do not explain this oddity.”


‘Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia’ by Henriette Thisted Horsdal et al. was published in JAMA Network Open at 15:00 UK time on Friday 1st November. 

DOI: 10.1001/jamanetworkopen.2019.14401


Declared interests

Prof David Curtis: “I have no conflict of interest to declare.”

Prof Paul Bebbington: “I have no interests to declare.” 

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