Air Pollution an Independent Risk Factor for Schizophrenia?

Childhood exposure to nitrogen dioxide (NO₂), a key component of air pollution and smog, appears to raise the risk schizophrenia, independent of genetic liability, results of a large population-based study show.

"In our study, a polygenic risk score for schizophrenia, based on common variants related to schizophrenia, could not account for the association between childhood NO₂ exposure and schizophrenia," first author Henriette Thisted Horsdal, PhD, Aarhus University in Denmark, told Medscape Medical News.

The study was published online November 1 in JAMA Network Open.

Genetics, Environment, or Both?

Schizophrenia is highly heritable. Recent studies have suggested that exposure to NO₂ during childhood raises the risk of schizophrenia later in life. Whether the increased risk associated with NO₂ exposure is owing to a greater genetic liability among those exposed to highest NO₂ levels is unclear.

To investigate, Horsdal and colleagues used interlinked data from multiple longitudinal, population-based registries with information on both residential exposure to NO₂ and genetic profiles.

The cohort included 23,355 people (51% male) born in Denmark between May 1981 and December 2002, who were followed up from age 10 until the first occurrence of schizophrenia, immigration, death, or the end of 2012, whichever came first.

During the study period, a total of 3531 individuals were diagnosed with schizophrenia. These individuals had greater childhood NO₂ exposure (mean 20.68 vs 18.63 μg/m³/day; P < .001) and a higher polygenic risk score for schizophrenia (mean 0.37 vs 0.00; P < .001).

A 10-μg/m³ increase in childhood daily NO₂ exposure (adjusted hazard ratio [AHR] 1.27; 95% confidence interval [CI], 1.19 to 1.35) and a 1-SD (standard deviation) increase in polygenic risk score for schizophrenia (AHR, 1.29; 95% CI, 1.23 - 1.35) were both associated with increased risk of schizophrenia.

Adjustment for polygenic risk score for schizophrenia only slightly attenuated the effect of childhood NO₂ exposure on schizophrenia risk (AHR, 1.23; 95% CI, 1.15 - 1.32).

These findings suggest that schizophrenia risk may be higher with increasing levels of childhood NO₂ exposure, Horsdal and colleagues say.

"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," they write.

A Proxy for Urban Living?

"This is an interesting paper carried out by a very respected group," E. Fuller Torrey, MD, a research psychiatrist specializing in schizophrenia who was not involved in the study, told Medscape Medical News.

"The bottom line is that the paper confirms the trend notable in research in recent years suggesting that environmental risk factors are much more important than genetic risk factors in causing this disease," said Torrey, from the Stanley Medical Research Institute in Kensington, Maryland.

However, Torrey also noted that in his opinion, "the paper does not suggest that nitrogen dioxide or other air pollutants cause schizophrenia. Rather, the air pollutants are proxies for urban living."

"Urban living is well known to be a major environmental risk factor for schizophrenia. Several correlates of urban living have been suggested as possibly causing schizophrenia, including greater exposure to some infectious agents in urban settings," said Torrey.

A study published last spring in JAMA Psychiatry showed psychotic experiences were significantly more common among adolescents with the highest exposure to NO₂, nitrogen oxides (NOx), and very small particulate matter (PM2.5), even after adjusting for known risk factors for psychosis.

In particular, as previously reported by Medscape Medical News, NO₂ and NOx together accounted for 60% of the association between living in an urban setting and experiencing psychosis during adolescence.

The study was funded in part by grants from The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) and BERTHA — the Danish Big Data Centre for Environment and Health, which was funded by the Novo Nordisk Foundation Challenge Program. Horsdal has disclosed no relevant financial relationships. Three study authors received grants from The Lundbeck Foundation and one reported being a paid lecturer and scientific advisor for H Lundbeck A/S. Torrey has disclosed no relevant financial relationships.

JAMA Netw Open. Published online November 1, 2019. Full text

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