Nitrogen Dioxide May Raise Schizophrenia Risk, Even When Accounting for Polygenic Factors

Industrial smoke emission from factory chimney under a stormy sky with foliage in the foreground.
Elevated risk for schizophrenia was linked to a 10 ug/m3 increase in daily childhood NO2 exposure (adjusted hazard ratio, 1.27) and a 1-SD increase in polygenic risk score (adjusted hazard ratio, 1.29).

Childhood exposure to nitrogen dioxide (NO2) — a frequent component of air pollution — elevates the risk for schizophrenia, according to the results of a Danish study published in JAMA Network Open.

Schizophrenia has a heritability of 70% to 85%, and genome-wide association studies indicate that it is highly polygenic, with multiple genes accounting for one-third to one-half of the genetic variation in the risk for the disorder.

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Henriette Thisted Horsdal, MSc, PhD, of the department of economics and business economics, Aarhus University, Denmark, and colleagues conducted a population-based cohort study of subjects with schizophrenia and a randomly selected subcohort from national registry data. They sought to determine the contributions of NO2 and polygenic factors to the risk of developing schizophrenia in individuals born between May 1, 1981 and December 31, 2005.

A gauge of NO2 exposure was created using a history of residential addresses for the first 10 years of the subject’s life. DNA obtained from blood spot samples from the Danish Newborn Screening Biobank was genotyped to calculate polygenic risk scores. Individuals were followed from their tenth birthday until hospital admission for schizophrenia, emigration, death, or end of follow-up (December 31, 2012). Statistical analyses included weighted Cox proportional hazards regression models, including adjustments for covariates, such as demographic factors, parental diagnoses, education, and employment.

The study population contained 23,355 individuals (51.3% men). Patients with schizophrenia (n=3531) had significantly (P <.001) higher levels of childhood NO2 exposure (20.68 vs 18.63 ug/m3/d, respectively) and higher polygenic risk scores for schizophrenia (0.37 vs. 0.00, respectively) than the subcohort (n=19,907).

Polygenic risk score was significantly associated with childhood NO2 exposure (p =.0782; 95% CI, 0.065-0.091; P <.001), explaining 0.61% of the variation and remaining significant for adjusted analyses. Elevated risk for schizophrenia was linked to a 10 ug/m3 increase in daily childhood NO2 exposure (adjusted hazard ratio, 1.27) and a 1-SD increase in polygenic risk score (adjusted hazard ratio, 1.29). In categorical analyses, these results displayed dose-response relationships. Adjusting for polygenic risk score only slightly attenuated the effect of childhood NO2 exposure on the risk for schizophrenia.

While the study used residential addresses during childhood to gauge NO2 exposure, it failed to capture exposure that may have occurred in other areas. In addition, the NO2 measures accounted for the years from birth to age 10 years but later exposure windows may be important as well. Nor does this study account for rare genetic mutations and copy number variants that may play a role in the development of schizophrenia.

The researchers declared, “Potential biological mechanisms for the association between air pollution and schizophrenia remain uncertain, but air pollutants have been purported to cause inflammation of the tissue of the nervous system, oxidative stress, microglial activation, protein aggregation, subclinical cerebrovascular disease, and disruption of the blood-brain barrier.”

Disclosure: Drs. Hougaard, Werge, and Borglum reported receiving grants from The Lundbeck Foundation. Dr. Werge also reported being a paid lecturer and scientific advisor for H. Lundbeck A/S. No other disclosures were reported.


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]. JAMA Network Open. doi:10.1001/jamanetworkopen.2019.14401