The association between childhood exposure to nitrogen dioxide (NO₂) and schizophrenia is only slightly confounded by increased genetic risk among individuals living in areas with higher levels of NO₂, according to a recently published article in Psychiatry.

To determine the associations between childhood NO₂ exposure and genetic liability for schizophrenia and the risk of developing schizophrenia, the study researchers utilized a national data registry of all individuals born in Denmark between May 1, 1981, and December 31, 2002. In addition to birthdate and gender, the registry contained information on residential exposure to NO₂, genetic profiles, and health-related data. The polygenic risk score of developing schizophrenia was calculated from genetic profiles. Participants were followed up from their 10th birthday until hospital admission for schizophrenia, emigration, death, or end of follow-up in December 2012.

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The case-cohort dataset contained 23,355 individuals, 51.3% of whom were men. The dataset was then divided between the 3531 individuals diagnosed with schizophrenia and 19,907 individuals without a schizophrenia diagnosis. Individuals diagnosed with schizophrenia had greater mean childhood exposure to NO₂ than those without (mean=20.68 vs mean=18.63, respectively) and greater mean polygenic risk score for schizophrenia (mean=0.37 vs mean=0.00, respectively). A significant correlation was detected between childhood exposure to NO₂ and polygenic risk score for schizophrenia (ρ=0.0782, P <.001). Greater risk of schizophrenia was significantly associated with higher polygenic risk score (adjusted hazard ratio=1.29) and increased childhood exposure to NO₂ (adjusted hazard ratio=1.27). Adjusting for polygenic risk score on the effect of childhood exposure to NO₂ slightly attenuated its effect on schizophrenia risk (adjusted hazard ratio=1.23).

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The study was limited by not including individuals diagnosed with schizophrenia who were only treated in primary care, a lack of information on NO₂ exposure, a limited participant age range for exposure measurements, a lack of variation in NO₂ levels that limits generalizability, and a lack of inclusion of rare variants and copy number variants in allele study.

The researchers concluded that the relationship between childhood exposure to NO₂ and schizophrenia is only slightly modified by polygenic risk score for schizophrenia. Furthermore, they state the “findings suggest that polygenic risk score based on common variants related to schizophrenia cannot account for the association between childhood NO₂ exposure and schizophrenia”.

Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Horsdal HT, Agerbo E, McGrath JJ, et al. Association of childhood exposure to nitrogen dioxide and polygenic risk score for schizophrenia with the risk of developing schizophrenia [published online November 1, 2019]. Psychiatry. doi: 10.1001/jamanetworkopen.2019.14401