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

Henriette Thisted Horsdal; Esben Agerbo; John Joseph McGrath; Bjarni Jóhann Vilhjálmsson; Sussie Antonsen; Ane Marie Closter; Allan Timmermann; Jakob Grove; Pearl L H Mok; Roger T Webb; Clive Eric Sabel; Ole Hertel; Torben Sigsgaard; Christian Erikstrup; David Michael Hougaard; Thomas Werge; Merete Nordentoft; Anders Dupont Børglum; Ole Mors; Preben Bo Mortensen; Jørgen Brandt; Camilla Geels; Carsten Bøcker Pedersen

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

Henriette Thisted Horsdal, Esben Agerbo, John Joseph McGrath, Bjarni Jóhann Vilhjálmsson, Sussie Antonsen, Ane Marie Closter, Allan Timmermann, Jakob Grove, Pearl L H Mok, Roger T Webb, Clive Eric Sabel, Ole Hertel, Torben Sigsgaard, Christian Erikstrup, David Michael Hougaard, Thomas Werge, Merete Nordentoft, Anders Dupont Børglum, Ole Mors, Preben Bo MortensenJørgen Brandt, Camilla Geels, Carsten Bøcker Pedersen

Department of Clinical Medicine

9 Citations (Scopus)

Abstract

Importance: 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. Objective: 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. Exposures: 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. Results: Of a total of 23355 individuals, 11976 (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..

Original language	English
Article number	e1914401
Journal	JAMA network open
Volume	2
Issue number	11
ISSN	2574-3805
DOIs	https://doi.org/10.1001/jamanetworkopen.2019.14401
Publication status	Published - 11 Nov 2019

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Horsdal, H. T., Agerbo, E., McGrath, J. J., Vilhjálmsson, B. J., Antonsen, S., Closter, A. M., Timmermann, A., Grove, J., Mok, P. L. H., Webb, R. T., Sabel, C. E., Hertel, O., Sigsgaard, T., Erikstrup, C., Hougaard, D. M., Werge, T., Nordentoft, M., Børglum, A. D., Mors, O., ... Pedersen, C. B. (2019). Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia. JAMA network open, 2(11), Article e1914401. https://doi.org/10.1001/jamanetworkopen.2019.14401

Horsdal, HT, Agerbo, E, McGrath, JJ, Vilhjálmsson, BJ, Antonsen, S, Closter, AM, Timmermann, A, Grove, J, Mok, PLH, Webb, RT, Sabel, CE, Hertel, O, Sigsgaard, T, Erikstrup, C, Hougaard, DM, Werge, T , Nordentoft, M, Børglum, AD, Mors, O, Mortensen, PB, Brandt, J, Geels, C & Pedersen, CB 2019, 'Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia', JAMA network open, vol. 2, no. 11, e1914401. https://doi.org/10.1001/jamanetworkopen.2019.14401

@article{278ed6e040b940f886ea421e9bc4cb60,

title = "Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia",

abstract = "Importance: 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. Objective: 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. Exposures: 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. Results: Of a total of 23355 individuals, 11976 (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..",

author = "Horsdal, {Henriette Thisted} and Esben Agerbo and McGrath, {John Joseph} and Vilhj{\'a}lmsson, {Bjarni J{\'o}hann} and Sussie Antonsen and Closter, {Ane Marie} and Allan Timmermann and Jakob Grove and Mok, {Pearl L H} and Webb, {Roger T} and Sabel, {Clive Eric} and Ole Hertel and Torben Sigsgaard and Christian Erikstrup and Hougaard, {David Michael} and Thomas Werge and Merete Nordentoft and B{\o}rglum, {Anders Dupont} and Ole Mors and Mortensen, {Preben Bo} and J{\o}rgen Brandt and Camilla Geels and Pedersen, {Carsten B{\o}cker}",

year = "2019",

month = nov,

day = "11",

doi = "10.1001/jamanetworkopen.2019.14401",

language = "English",

volume = "2",

journal = "JAMA network open",

issn = "2574-3805",

publisher = "American Medical Association",

number = "11",

}

TY - JOUR

T1 - Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia

AU - Horsdal, Henriette Thisted

AU - Agerbo, Esben

AU - McGrath, John Joseph

AU - Vilhjálmsson, Bjarni Jóhann

AU - Antonsen, Sussie

AU - Closter, Ane Marie

AU - Timmermann, Allan

AU - Grove, Jakob

AU - Mok, Pearl L H

AU - Webb, Roger T

AU - Sabel, Clive Eric

AU - Hertel, Ole

AU - Sigsgaard, Torben

AU - Erikstrup, Christian

AU - Hougaard, David Michael

AU - Werge, Thomas

AU - Nordentoft, Merete

AU - Børglum, Anders Dupont

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Brandt, Jørgen

AU - Geels, Camilla

AU - Pedersen, Carsten Bøcker

PY - 2019/11/11

Y1 - 2019/11/11

N2 - Importance: 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. Objective: 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. Exposures: 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. Results: Of a total of 23355 individuals, 11976 (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..

AB - Importance: 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. Objective: 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. Exposures: 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. Results: Of a total of 23355 individuals, 11976 (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..

U2 - 10.1001/jamanetworkopen.2019.14401

DO - 10.1001/jamanetworkopen.2019.14401

M3 - Journal article

C2 - 31675084

SN - 2574-3805

VL - 2

JO - JAMA network open

JF - JAMA network open

IS - 11

M1 - e1914401

ER -

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

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