The role of genetic liability in the association of urbanicity at birth and during upbringing with schizophrenia in Denmark

Background Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case–control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia. Methods Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis. Results Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01–1.40], but not at birth (OR 1.09, 95% CI 0.95–1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18–2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97–1.78; overall p = 0.148). Conclusions While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia.

[1]  M. Munafo,et al.  Schizophrenia and neighbourhood deprivation , 2016, Translational Psychiatry.

[2]  O. Mors,et al.  Influence of Polygenic Risk Scores on the Association Between Infections and Schizophrenia , 2016, Biological Psychiatry.

[3]  Robert M. Maier,et al.  High loading of polygenic risk in cases with chronic schizophrenia , 2016, Molecular Psychiatry.

[4]  P. Visscher,et al.  Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women. , 2016, JAMA psychiatry.

[5]  P. Lichtenstein,et al.  Schizophrenia and subsequent neighborhood deprivation: revisiting the social drift hypothesis using population, twin and molecular genetic data , 2016, Translational psychiatry.

[6]  C. Pedersen.  Persons with schizophrenia migrate towards urban areas due to the development of their disorder or its prodromata , 2015, Schizophrenia Research.

[7]  Vincent Frouin,et al.  Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence. , 2015, JAMA psychiatry.

[8]  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.

[9]  P. Lichtenstein,et al.  Does population density and neighborhood deprivation predict schizophrenia? A nationwide Swedish family-based study of 2.4 million individuals. , 2015, Schizophrenia bulletin.

[10]  S. Sarkar,et al.  Urban living and psychosis--an overview. , 2014, Asian journal of psychiatry.

[11]  N. Wray,et al.  Genetic predisposition to schizophrenia associated with increased use of cannabis , 2014, Molecular Psychiatry.

[12]  N. Wray,et al.  Research review: Polygenic methods and their application to psychiatric traits. , 2014, Journal of child psychology and psychiatry, and allied disciplines.

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

[14]  A. Bertelsen,et al.  A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders. , 2014, JAMA psychiatry.

[15]  C. Correll,et al.  The validity of the schizophrenia diagnosis in the Danish Psychiatric Central Research Register is good. , 2013, Danish medical journal.

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

[17]  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.

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

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

[20]  P. Visscher,et al.  Sporadic cases are the norm for complex disease , 2010, European Journal of Human Genetics.

[21]  S. Cole,et al.  Illustrating bias due to conditioning on a collider. , 2010, International journal of epidemiology.

[22]  J. Waddington,et al.  Schizophrenia and the city: A review of literature and prospective study of psychosis and urbanicity in Ireland , 2010, Schizophrenia Research.

[23]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[24]  P. Mortensen,et al.  Psychiatric family history and schizophrenia risk in Denmark: which mental disorders are relevant? , 2009, Psychological Medicine.

[25]  Michaeline Bresnahan,et al.  Psychosis and place. , 2008, Epidemiologic reviews.

[26]  Marko Elovainio,et al.  Temperament and Migration Patterns in Finland , 2008, Psychological science.

[27]  T. Hansen,et al.  Reliability of clinical ICD-10 diagnoses among electroconvulsive therapy patients with chronic affective disorders , 2008 .

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

[29]  T. Price,et al.  Gene–environment correlations: a review of the evidence and implications for prevention of mental illness , 2007, Molecular Psychiatry.

[30]  E. Cantor-Graae,et al.  Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study , 2007, Psychological Medicine.

[31]  James Scott,et al.  Urban birth and risk of schizophrenia: a worrying example of epidemiology where the data are stronger than the hypotheses , 2006, Epidemiology and Psychiatric Sciences.

[32]  P. Mortensen,et al.  The Danish Civil Registration System. A cohort of eight million persons. , 2006, Danish medical bulletin.

[33]  P. Mortensen,et al.  Why factors rooted in the family may solely explain the urban-rural differences in schizophrenia risk estimates , 2006, Epidemiology and Psychiatric Sciences.

[34]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[35]  P. Mortensen,et al.  Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals? , 2006, American journal of epidemiology.

[36]  J. Os,et al.  The schizophrenia envirome , 2005, Current opinion in psychiatry.

[37]  Nicholas G Martin,et al.  Choice of Residential Location: Chance, Family Influences, or Genes? , 2005, Twin Research and Human Genetics.

[38]  A. Jablensky,et al.  Genetic epidemiology of schizophrenia: phenotypes, risk factors, and reproductive behavior. , 2003, The American journal of psychiatry.

[39]  P. Mortensen,et al.  Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. , 2001, Archives of general psychiatry.

[40]  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.

[41]  J. Suvisaari,et al.  Decreasing seasonal variation of births in schizophrenia , 2000, Psychological Medicine.

[42]  P. Andersen,et al.  Effects of family history and place and season of birth on the risk of schizophrenia. , 1999, The New England journal of medicine.

[43]  R. Murray,et al.  Urbanization and psychosis: a study of 1942–1978 birth cohorts in The Netherlands , 1998, Psychological Medicine.

[44]  H Freeman,et al.  Schizophrenia and City Residence , 1994, British Journal of Psychiatry.

[45]  A. David,et al.  Schizophrenia and city life , 1992, The Lancet.

[46]  W. Eaton.  Residence, social class, and schizophrenia. , 1974, Journal of health and social behavior.

[47]  M. Terris,et al.  The drift hypothesis and socioeconomic differentials in schizophrenia. , 1956, American journal of public health and the nation's health.

[48]  L. Petersen,et al.  Paternal age at birth of first child and risk of schizophrenia. , 2011, The American journal of psychiatry.

[49]  R. Faris,et al.  Mental Disorders in Urban Areas: An Ecological Study of Schizophrenia and Other Psychoses , 1939 .

[50]  R. Faris.  Mental disorders in urban areas , 1939 .