Skip to main content Accessibility help

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

  • D. Paksarian (a1), B. B. Trabjerg (a2) (a3) (a4), K. R. Merikangas (a1), O. Mors (a3) (a5), A. D. Børglum (a3) (a5) (a6), D. M. Hougaard (a7), J. J. McGrath (a2) (a8), C. B. Pedersen (a2) (a3) (a4), P. B. Mortensen (a2) (a3) (a4) and E. Agerbo (a2) (a3) (a4)...



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.


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.


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).


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.


Corresponding author

*Address for correspondence: D. Paksarian, Genetic Epidemiology Research Branch, National Institute of Mental Health, 35A Convent Drive, MSC#3720, Bethesda, MD 20892, USA. (Email:


Hide All
Agerbo, E, Mortensen, PB, Wiuf, C, Pedersen, MS, McGrath, J, Hollegaard, MV, Norgaard-Pedersen, B, Hougaard, DM, Mors, O, Pedersen, CB (2012). Modelling the contribution of family history and variation in single nucleotide polymorphisms to risk of schizophrenia: a Danish national birth cohort-based study. Schizophrenia Research 134, 246252.
Agerbo, E, Sullivan, PF, Vilhjalmsson, BJ, Pedersen, CB, Mors, O, Borglum, AD, Hougaard, DM, Hollegaard, MV, Meier, S, Mattheisen, M, Ripke, S, Wray, NR, Mortensen, PB (2015). Polygenic risk score, parental socioeconomic status, family history of psychiatric disorders, and the risk for schizophrenia: a Danish population-based study and meta-analysis. JAMA Psychiatry 72, 635641.
Benros, ME, Trabjerg, BB, Meier, S, Mattheisen, M, Mortensen, PB, Mors, O, Borglum, AD, Hougaard, DM, Norgaard-Pedersen, B, Nordentoft, M, Agerbo, E (2016). Influence of polygenic risk scores on the association between infections and schizophrenia. Biological Psychiatry 80, 609616.
Borglum, AD, Demontis, D, Grove, J, Pallesen, J, Hollegaard, MV, Pedersen, CB, Hedemand, A, Mattheisen, M, GROUP Investigators, Uitterlinden, A, Nyegaard, M, Orntoft, T, Wiuf, C, Didriksen, M, Nordentoft, M, Nothen, MM, Rietschel, M, Ophoff, RA, Cichon, S, Yolken, RH, Hougaard, DM, Mortensen, PB, Mors, O (2014). Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Molecular Psychiatry 19, 325333.
Cantor-Graae, E, Pedersen, CB (2007). Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study. Psychological Medicine 37, 485494.
Cole, SR, Platt, RW, Schisterman, EF, Chu, HT, Westreich, D, Richardson, D, Poole, C (2010). Illustrating bias due to conditioning on a collider. International Journal of Epidemiology 39, 417420.
Eaton, WW (1974). Residence, social class, and schizophrenia. Journal of Health and Social Behavior 15, 289299.
Faris, REL, Dunham, HW (1939). Mental Disorders in Urban Areas; an Ecological Study of Schizophrenia and Other Psychoses. Hafner: New York.
Freeman, H (1994) Schizophrenia and city residence. British Journal of Psychiatry 164, 3950.
French, L, Gray, C, Leonard, G, Perron, M, Pike, GB, Richer, L, Seguin, JR, Veillette, S, Evans, CJ, Artiges, E, Banaschewski, T, Bokde, AL, Bromberg, U, Bruehl, R, Buchel, C, Cattrell, A, Conrod, PJ, Flor, H, Frouin, V, Gallinat, J, Garavan, H, Gowland, P, Heinz, A, Lemaitre, H, Martinot, JL, Nees, F, Orfanos, DP, Pangelinan, MM, Poustka, L, Rietschel, M, Smolka, MN, Walter, H, Whelan, R, Timpson, NJ, Schumann, G, Smith, GD, Pausova, Z, Paus, T (2015). Early Cannabis use, polygenic risk score for schizophrenia, and brain maturation in adolescence. JAMA Psychiatry 72, 10021011.
Gage, S, Smith, GD, Munafò, M (2016). Schizophrenia and neighbourhood deprivation. Translational Psychiatry 6, e979.
Jablensky, AV, Kalaydjieva, LV (2003). Genetic epidemiology of schizophrenia: phenotypes, risk factors, and reproductive behavior. American Journal of Psychiatry, 160, 425429.
Jaffee, SR, Price, TS (2007). Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. Molecular Psychiatry, 12, 432442.
Jakobsen, KD, Hansen, T, Dam, H, Larsen, EB, Gether, U, Werge, T (2008). Reliability of clinical ICD-10 diagnoses among electroconvulsive therapy patients with chronic affective disorders. European Journal of Psychiatry 22, 161172.
Jokela, M, Elovainio, M, Kivimaki, M, Keltikangas-Jarvinen, L (2008). Temperament and Migration Patterns in Finland. Psychological Science 19, 831837.
Kelly, BD, O'Callaghan, E, Waddington, JL, Feeney, L, Browne, S, Scully, PJ, Clarke, M, Quinn, JF, McTigue, O, Morgan, MG, Kinsella, A, Larkin, C (2010). Schizophrenia and the city: a review of literature and prospective study of psychosis and urbanicity in Ireland. Schizophrenia Research 116, 7589.
Lapouse, R, Monk, MA, Terris, M (1956). The drift hypothesis and socioeconomic differentials in schizophrenia. American Journal of Public Health and the Nations Health 46, 978986.
Lewis, G, David, A, Andreasson, S, Allebeck, P (1992). Schizophrenia and city life. Lancet 340, 137140.
Marcelis, M, Navarro-Mateu, F, Murray, R, Selten, JP, Van Os, J (1998). Urbanization and psychosis: a study of 1942–1978 birth cohorts in The Netherlands. Psychological Medicine 28, 871879.
March, D, Hatch, SL, Morgan, C, Kirkbride, JB, Bresnahan, M, Fearon, P, Susser, E (2008). Psychosis and place. Epidemiologic Reviews 30, 84100.
McGrath, J, Scott, J (2006). Urban birth and risk of schizophrenia: a worrying example of epidemiology where the data are stronger than the hypotheses. Epidemiologia E Psichiatria Sociale 15, 243246.
Mehta, D, Tropf, FC, Gratten, J, Bakshi, A, Zhu, ZH, Bacanu, SA, Hemani, G, Magnusson, PKE, Barban, N, Esko, T, Metspalu, A, Snieder, H, Mowry, BJ, Kendler, KS, Yang, J, Visscher, PM, Mcgrath, JJ, Mills, MC, Wray, NR, Lee, SH, Consortium PG, Study LC & TWINSUK (2016). Evidence for genetic overlap between schizophrenia and age at first birth in women. JAMA Psychiatry, 73, 497505.
Meier, SM, Agerbo, E, Maier, R, Pedersen, CB, Lang, M, Grove, J, Hollegaard, MV, Demontis, D, Trabjerg, BB, Hjorthoj, C, Ripke, S, Degenhardt, F, Nothen, MM, Rujescu, D, Maier, W, Moo, D, Werge, T, Mors, O, Hougaard, DM, Borglum, AD, Wray, NR, Rietschel, M, Nordentoft, M, Mortensen, PB, Mattheisen, M (2016). High loading of polygenic risk in cases with chronic schizophrenia. Molecular Psychiatry 21, 969974.
Mors, O, Perto, GP, Mortensen, PB (2011). The Danish Psychiatric Central Research Register. Scandinavian Journal of Public Health 39, 5457.
Mortensen, PB, Pedersen, CB, Westergaard, T, Wohlfahrt, J, Ewald, H, Mors, O, Andersen, PK, Melbye, M (1999). Effects of family history and place and season of birth on the risk of schizophrenia. New England Journal of Medicine 340, 603608.
Mortensen, PB, Pedersen, MG, Pedersen, CB (2010). Psychiatric family history and schizophrenia risk in Denmark: which mental disorders are relevant? Psychological Medicine 40, 201210.
Norgaard-Pedersen, B, Hougaard, DM (2007). Storage policies and use of the Danish Newborn Screening Biobank. Journal of Inherited Metabolic Disease 30, 530536.
Padhy, SK, Sarkar, S, Davuluri, T, Patra, BN (2014). Urban living and psychosis – an overview. Asian Journal of Psychiatry 12, 1722.
Pedersen, CB (2015). Persons with schizophrenia migrate towards urban areas due to the development of their disorder or its prodromata. Schizophrenia Research 168, 204208.
Pedersen, CB, Gotzsche, H, Moller, JO, Mortensen, PB (2006). The Danish Civil Registration System – a cohort of eight million persons. Danish Medical Bulletin 53, 441449.
Pedersen, CB, Mors, O, Bertelsen, A, Waltoft, BL, Agerbo, E, Mcgrath, JJ, Mortensen, PB, Eaton, WW (2014). A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders. JAMA Psychiatry 71, 573581.
Pedersen, CB, Mortensen, PB (2001a). Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Archives of General Psychiatry 58, 10391046.
Pedersen, CB, Mortensen, PB (2001b). Family history, place and season of birth as risk factors for schizophrenia in Denmark: a replication and reanalysis. British Journal of Psychiatry 179, 4652.
Pedersen, CB, Mortensen, PB (2006a). Are the cause(s) responsible for urban-rural differences in schizophrenia risk rooted in families or in individuals?. American Journal of Epidemiology 163, 971978.
Pedersen, CB, Mortensen, PB (2006b). Why factors rooted in the family may solely explain the urban-rural differences in schizophrenia risk estimates. Epidemiologia E Psichiatria Sociale 15, 247251.
Petersen, L, Mortensen, PB, Pedersen, CB (2011). Paternal age at birth of first child and risk of schizophrenia. American Journal of Psychiatry 168, 8288.
Power, RA, Verweij, KJH, Zuhair, M, Montgomery, GW, Henders, AK, Heath, AC, Madden, PAF, Medland, SE, Wray, NR, Martin, NG (2014). Genetic predisposition to schizophrenia associated with increased use of cannabis. Molecular Psychiatry 19, 12011204.
Price, AL, Patterson, NJ, Plenge, RM, Weinblatt, ME, Shadick, NA, Reich, D (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics 38, 904909.
Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P, Ruderfer, DM, Mcquillin, A, Morris, DW, O'Dushlaine, CT (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748752.
Sariaslan, A, Fazel, S, D'Onofrio, BM, Langstrom, N, Larsson, H, Bergen, SE, Kuja-Halkola, R, Lichtenstein, P (2016). Schizophrenia and subsequent neighborhood deprivation: revisiting the social drift hypothesis using population, twin and molecular genetic data. Translational Psychiatry 6, e796.
Sariaslan, A, Larsson, H, D'Onofrio, B, Langstrom, N, Fazel, S, Lichtenstein, P (2015) Does population density and neighborhood deprivation predict schizophrenia? A nationwide Swedish family-based study of 2.4 million individuals. Schizophrenia Bulletin 41, 494502.
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421427.
Suvisaari, JM, Haukka, JK, Tanskanen, AJ, Lonnqvist, JK (2000). Decreasing seasonal variation of births in schizophrenia. Psychological Medicine 30, 315324.
Uggerby, P, Ostergaard, SD, Roge, R, Correll, CU, Nielsen, J (2013). The validity of the schizophrenia diagnosis in the Danish Psychiatric Central Research Register is good. Danish Medical Journal 60, p A4578.
Van Os, J, Kenis, G, Rutten, BPF (2010) The environment and schizophrenia. Nature 468, 203212.
Van Os, J, Krabbendam, L, Myin-Germeys, I, Delespaul, P (2005). The schizophrenia envirome. Current Opinion in Psychiatry 18, 141145.
Whitfield, JB, Zhu, G, Heath, AC, Martin, NG (2005). Choice of residential location: chance, family influences, or genes? Twin Research and Human Genetics 8, 2226.
Wray, NR, Lee, SH, Mehta, D, Vinkhuyzen, AA, Dudbridge, F, Middeldorp, CM (2014). Research review: polygenic methods and their application to psychiatric traits. J Child Psychol Psychiatry 55, 10681087.
Yang, JA, Visscher, PM, Wray, NR (2010). Sporadic cases are the norm for complex disease. European Journal of Human Genetics 18, 10391043.


Type Description Title
Supplementary materials

Paksarian supplementary material

 PDF (137 KB)
137 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed