Association Between Childhood Green Space, Genetic Liability, and the Incidence of Schizophrenia.

Childhood exposure to green space has previously been associated with lower risk of developing schizophrenia later in life. It is unclear whether this association is mediated by genetic liability or whether the 2 risk factors work additively. Here, we investigate possible gene-environment associations with the hazard ratio (HR) of schizophrenia by combining (1) an estimate of childhood exposure to residential-level green space based on the normalized difference vegetation index (NDVI) from Landsat satellite images, with (2) genetic liability estimates based on polygenic risk scores for 19 746 genotyped individuals from the Danish iPSYCH sample. We used information from the Danish registers of health, residential address, and socioeconomic status to adjust HR estimates for established confounders, ie, parents' socioeconomic status, and family history of mental illness. The adjusted HRs show that growing up surrounded by the highest compared to the lowest decile of NDVI was associated with a 0.52-fold (95% confidence interval [CI]: 0.40 to 0.66) lower schizophrenia risk, and children with the highest polygenic risk score had a 1.24-fold (95% CI: 1.18 to 1.30) higher schizophrenia risk. We found that NDVI explained 1.45% (95% CI: 1.07 to 1.90) of the variance on the liability scale, while polygenic risk score for schizophrenia explained 1.01% (95% CI: 0.77 to 1.46). Together they explained 2.40% (95% CI: 1.99 to 3.07) with no indication of a gene-environment interaction (P = .29). Our results suggest that risk of schizophrenia is associated additively with green space exposure and genetic liability, and provide no support for an environment-gene interaction between NDVI and schizophrenia.

[1]  P. Mortensen,et al.  The association between early-onset schizophrenia with employment, income, education, and cohabitation status: nationwide study with 35 years of follow-up , 2019, Social Psychiatry and Psychiatric Epidemiology.

[2]  R. Yolken,et al.  Schizophrenia as a pseudogenetic disease: A call for more gene-environmental studies , 2019, Psychiatry Research.

[3]  Chih-Da Wu,et al.  Association Between Surrounding Greenness and Schizophrenia: A Taiwanese Cohort Study , 2019, International journal of environmental research and public health.

[4]  M. Prince,et al.  A review of the 10/66 dementia research group , 2018, Social Psychiatry and Psychiatric Epidemiology.

[5]  James G. Scott,et al.  Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016 , 2018, Schizophrenia bulletin.

[6]  Andy P. Jones,et al.  The health benefits of the great outdoors: A systematic review and meta-analysis of greenspace exposure and health outcomes , 2018, Environmental research.

[7]  Evangelos Vassos,et al.  Transforming summary statistics from logistic regression to the liability scale: application to genetic and environmental risk scores , 2018, bioRxiv.

[8]  L. Arge,et al.  35.3 CHILDHOOD EXPOSURE TO GREEN SPACE – A NOVEL RISK-DECREASING MECHANISM FOR SCHIZOPHRENIA? , 2018, Schizophrenia Bulletin.

[9]  Bjarni V. Halldórsson,et al.  The nature of nurture: Effects of parental genotypes , 2017, Science.

[10]  R. McCormick.  Does Access to Green Space Impact the Mental Well‐being of Children: A Systematic Review , 2017, Journal of pediatric nursing.

[11]  K. Merikangas,et al.  The role of genetic liability in the association of urbanicity at birth and during upbringing with schizophrenia in Denmark , 2017, Psychological Medicine.

[12]  M. Daly,et al.  The iPSYCH2012 case–cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders , 2017, Molecular Psychiatry.

[13]  P. Visscher,et al.  Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores , 2015, bioRxiv.

[14]  Esben Agerbo,et al.  Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia: A Danish Population-Based Study and Meta-analysis. , 2015, JAMA psychiatry.

[15]  X. Basagaña,et al.  Green spaces and cognitive development in primary schoolchildren , 2015, Proceedings of the National Academy of Sciences.

[16]  F. Laden,et al.  A Review of the Health Benefits of Greenness , 2015, Current Epidemiology Reports.

[17]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[18]  H. Frumkin,et al.  Nature and health. , 2014, Annual review of public health.

[19]  Eric S. Lander,et al.  A polygenic burden of rare disruptive mutations in schizophrenia , 2014, Nature.

[20]  K. Rascati,et al.  Estimating the direct and indirect costs for community‐dwelling patients with schizophrenia , 2013 .

[21]  G. Rook.  Regulation of the immune system by biodiversity from the natural environment: An ecosystem service essential to health , 2013, Proceedings of the National Academy of Sciences.

[22]  R A Ophoff,et al.  Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci , 2013, Molecular Psychiatry.

[23]  Lars Arge,et al.  Fast generation of multiple resolution instances of raster data sets , 2012, SIGSPATIAL/GIS.

[24]  R. Murray,et al.  Meta-analysis of the association of urbanicity with schizophrenia. , 2012, Schizophrenia bulletin.

[25]  P. Visscher,et al.  A Better Coefficient of Determination for Genetic Profile Analysis , 2012, Genetic epidemiology.

[26]  J. Sebat,et al.  CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics , 2012, Cell.

[27]  C. Wiuf,et al.  Modelling the contribution of family history and variation in single nucleotide polymorphisms to risk of schizophrenia: A Danish national birth cohort-based study , 2012, Schizophrenia Research.

[28]  Nicholas L Smith,et al.  Validation of the normalized difference vegetation index as a measure of neighborhood greenness. , 2011, Annals of epidemiology.

[29]  L. Thygesen,et al.  Danish registers on personal labour market affiliation , 2011, Scandinavian journal of public health.

[30]  O. Mors,et al.  The Danish Psychiatric Central Research Register , 2011, Scandinavian journal of public health.

[31]  C. Pedersen,et al.  The Danish Civil Registration System , 2011, Scandinavian journal of public health.

[32]  Vibeke Jensen,et al.  Danish education registers , 2011, Scandinavian journal of public health.

[33]  Jim van Os,et al.  The environment and schizophrenia , 2010, Nature.

[34]  D. Hougaard,et al.  Storage policies and use of the Danish Newborn Screening Biobank , 2007, Journal of Inherited Metabolic Disease.

[35]  Patrick F Sullivan,et al.  Recurrence risks for schizophrenia in a Swedish National Cohort , 2006, Psychological Medicine.

[36]  P. Sullivan,et al.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. , 2003, Archives of general psychiatry.

[37]  P. Mortensen,et al.  Family history, place and season of birth as risk factors for schizophrenia in Denmark: A replication and reanalysis , 2001, British Journal of Psychiatry.

[38]  Bryan Langholz,et al.  Exposure Stratified Case-Cohort Designs , 2000, Lifetime data analysis.

[39]  S. R. Searle,et al.  Population Marginal Means in the Linear Model: An Alternative to Least Squares Means , 1980 .

[40]  Bhramar Mukherjee,et al.  Current Challenges and New Opportunities for Gene-Environment Interaction Studies of Complex Diseases. , 2017, American journal of epidemiology.

[41]  C. V. D. Bosch,et al.  Challenges and strategies for urban green-space planning in cities undergoing densification: A review , 2015 .

[42]  Magdalena van den Berg,et al.  Health benefits of green spaces in the living environment: A systematic review of epidemiological studies , 2015 .