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JAMA Netw Open. 2019 Nov 1;2(11):e1914401. doi: 10.1001/jamanetworkopen.2019.14401.

Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia.

Author information

Department of Economics and Business Economics, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
Big Data Centre for Environment and Health (BERTHA), Aarhus University, Roskilde, Denmark.
Centre for Integrated Register-based Research, CIRRAU, Aarhus University, Aarhus, Denmark.
Queensland Brain Institute, The University of Queensland, St Lucia, Queensland, Australia.
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia.
Department of Biomedicine and Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
Center for Genomics and Personalized Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.
Centre for Mental Health and Safety, Division of Psychology and Mental Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
Department of Environmental Science, Aarhus University, Aarhus, Denmark.
Department of Public Health, Aarhus University, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Institute of Biological Psychiatry, Copenhagen Mental Health Services, Copenhagen, Denmark.
Mental Health Centre Copenhagen, Capital Region of Denmark, Copenhagen University Hospital, Copenhagen, Denmark.
Psychosis Research Unit, Aarhus University Hospital Psychiatry, Aarhus, Denmark.



Schizophrenia is a highly heritable psychiatric disorder, and recent studies have suggested that exposure to nitrogen dioxide (NO2) during childhood is associated with an elevated risk of subsequently developing schizophrenia. However, it is not known whether the increased risk associated with NO2 exposure is owing to a greater genetic liability among those exposed to highest NO2 levels.


To examine the associations between childhood NO2 exposure and genetic liability for schizophrenia (as measured by a polygenic risk score), and risk of developing schizophrenia.

Design, Setting, and Participants:

Population-based cohort study including individuals with schizophrenia (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code F20) and a randomly selected subcohort. Using national registry data, all individuals born in Denmark between May 1, 1981, and December 31, 2002, were followed up from their 10th birthday until the first occurrence of schizophrenia, emigration, death, or December 31, 2012, whichever came first. Statistical analyses were conducted between October 24, 2018, and June 17, 2019.


Individual exposure to NO2 during childhood estimated as mean daily exposure to NO2 at residential addresses from birth to the 10th birthday. Polygenic risk scores were calculated as the weighted sum of risk alleles at selected single-nucleotide polymorphisms based on genetic material obtained from dried blood spot samples from the Danish Newborn Screening Biobank and on the Psychiatric Genomics Consortium genome-wide association study summary statistics file.

Main Outcomes and Measures:

The main outcome was schizophrenia. Weighted Cox proportional hazards regression models were fitted to estimate adjusted hazard ratios (AHRs) for schizophrenia with 95% CIs according to the exposures.


Of a total of 23 355 individuals, 11 976 (51.3%) were male and all had Danish-born parents. During the period of the study, 3531 were diagnosed with schizophrenia. Higher polygenic risk scores were correlated with higher childhood NO2 exposure (ρ = 0.0782; 95% CI, 0.065-0.091; P < .001). A 10-μg/m3 increase in childhood daily NO2 exposure (AHR, 1.23; 95% CI, 1.15-1.32) and a 1-SD increase in polygenic risk score (AHR, 1.29; 95% CI, 1.23-1.35) were independently associated with increased schizophrenia risk.

Conclusions and Relevance:

These findings suggest that the apparent association between NO2 exposure and schizophrenia is only slightly confounded by a higher polygenic risk score for schizophrenia among individuals living in areas with greater NO2. The findings demonstrate the utility of including polygenic risk scores in epidemiologic studies.

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