Hostname: page-component-78c5997874-xbtfd Total loading time: 0 Render date: 2024-11-16T18:24:24.104Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  29 June 2017

D. Paksarian ,
B. B. Trabjerg ,
K. R. Merikangas ,
O. Mors ,
A. D. Børglum ,
D. M. Hougaard ,
J. J. McGrath ,
C. B. Pedersen ,
P. B. Mortensen  and
E. Agerbo
D. Paksarian*
Affiliation:
Genetic Epidemiology Research Branch, National Institute of Mental Health, Bethesda, MD, USA
B. B. Trabjerg
Affiliation:
NCRR-National Center for Register-Based Research, Business and Social Sciences, Aarhus University, Aarhus, Denmark The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark CIRRAU–Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark
K. R. Merikangas
Affiliation:
Genetic Epidemiology Research Branch, National Institute of Mental Health, Bethesda, MD, USA
O. Mors
Affiliation:
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark Department P, Aarhus University Hospital, Risskov, Denmark
A. D. Børglum
Affiliation:
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark Department P, Aarhus University Hospital, Risskov, Denmark Department of Biomedicine and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
D. M. Hougaard
Affiliation:
Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark
J. J. McGrath
Affiliation:
NCRR-National Center for Register-Based Research, Business and Social Sciences, Aarhus University, Aarhus, Denmark Queensland Brain Institute, The University of Queensland, St Lucia, Australia
C. B. Pedersen
Affiliation:
NCRR-National Center for Register-Based Research, Business and Social Sciences, Aarhus University, Aarhus, Denmark The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark CIRRAU–Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark
P. B. Mortensen
Affiliation:
NCRR-National Center for Register-Based Research, Business and Social Sciences, Aarhus University, Aarhus, Denmark The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark CIRRAU–Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark
E. Agerbo
Affiliation:
NCRR-National Center for Register-Based Research, Business and Social Sciences, Aarhus University, Aarhus, Denmark The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark CIRRAU–Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark
*
*Address for correspondence: D. Paksarian, Genetic Epidemiology Research Branch, National Institute of Mental Health, 35A Convent Drive, MSC#3720, Bethesda, MD 20892, USA. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

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.

Keywords

Epidemiologypolygenic risk scoreschizophreniaurbanicityselective migration
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 2 , January 2018 , pp. 305 - 314
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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, 246–252.Google Scholar
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, 635–641.CrossRefGoogle ScholarPubMed
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, 609–616.Google Scholar
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, 325–333.Google Scholar
Cantor-Graae, E, Pedersen, CB (2007). Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study. Psychological Medicine 37, 485–494.CrossRefGoogle ScholarPubMed
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, 417–420.Google Scholar
Eaton, WW (1974). Residence, social class, and schizophrenia. Journal of Health and Social Behavior 15, 289–299.Google Scholar
Faris, REL, Dunham, HW (1939). Mental Disorders in Urban Areas; an Ecological Study of Schizophrenia and Other Psychoses. Hafner: New York.Google Scholar
Freeman, H (1994) Schizophrenia and city residence. British Journal of Psychiatry 164, 39–50.Google Scholar
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, 1002–1011.CrossRefGoogle ScholarPubMed
Gage, S, Smith, GD, Munafò, M (2016). Schizophrenia and neighbourhood deprivation. Translational Psychiatry 6, e979.CrossRefGoogle ScholarPubMed
Jablensky, AV, Kalaydjieva, LV (2003). Genetic epidemiology of schizophrenia: phenotypes, risk factors, and reproductive behavior. American Journal of Psychiatry, 160, 425–429.Google Scholar
Jaffee, SR, Price, TS (2007). Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. Molecular Psychiatry, 12, 432–442.Google Scholar
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, 161–172.Google Scholar
Jokela, M, Elovainio, M, Kivimaki, M, Keltikangas-Jarvinen, L (2008). Temperament and Migration Patterns in Finland. Psychological Science 19, 831–837.Google Scholar
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, 75–89.CrossRefGoogle ScholarPubMed
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, 978–986.Google Scholar
Lewis, G, David, A, Andreasson, S, Allebeck, P (1992). Schizophrenia and city life. Lancet 340, 137–140.Google Scholar
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, 871–879.Google Scholar
March, D, Hatch, SL, Morgan, C, Kirkbride, JB, Bresnahan, M, Fearon, P, Susser, E (2008). Psychosis and place. Epidemiologic Reviews 30, 84–100.Google Scholar
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, 243–246.Google Scholar
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, 497–505.Google Scholar
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, 969–974.Google Scholar
Mors, O, Perto, GP, Mortensen, PB (2011). The Danish Psychiatric Central Research Register. Scandinavian Journal of Public Health 39, 54–57.CrossRefGoogle ScholarPubMed
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, 603–608.Google Scholar
Mortensen, PB, Pedersen, MG, Pedersen, CB (2010). Psychiatric family history and schizophrenia risk in Denmark: which mental disorders are relevant? Psychological Medicine 40, 201–210.Google Scholar
Norgaard-Pedersen, B, Hougaard, DM (2007). Storage policies and use of the Danish Newborn Screening Biobank. Journal of Inherited Metabolic Disease 30, 530–536.Google Scholar
Padhy, SK, Sarkar, S, Davuluri, T, Patra, BN (2014). Urban living and psychosis – an overview. Asian Journal of Psychiatry 12, 17–22.Google Scholar
Pedersen, CB (2015). Persons with schizophrenia migrate towards urban areas due to the development of their disorder or its prodromata. Schizophrenia Research 168, 204–208.Google Scholar
Pedersen, CB, Gotzsche, H, Moller, JO, Mortensen, PB (2006). The Danish Civil Registration System – a cohort of eight million persons. Danish Medical Bulletin 53, 441–449.Google Scholar
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, 573–581.CrossRefGoogle ScholarPubMed
Pedersen, CB, Mortensen, PB (2001a). Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Archives of General Psychiatry 58, 1039–1046.Google Scholar
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, 46–52.Google Scholar
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, 971–978.Google Scholar
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, 247–251.Google Scholar
Petersen, L, Mortensen, PB, Pedersen, CB (2011). Paternal age at birth of first child and risk of schizophrenia. American Journal of Psychiatry 168, 82–88.CrossRefGoogle ScholarPubMed
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, 1201–1204.Google Scholar
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, 904–909.Google Scholar
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, 748–752.Google Scholar
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.Google Scholar
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, 494–502.CrossRefGoogle ScholarPubMed
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.CrossRefGoogle Scholar
Suvisaari, JM, Haukka, JK, Tanskanen, AJ, Lonnqvist, JK (2000). Decreasing seasonal variation of births in schizophrenia. Psychological Medicine 30, 315–324.Google Scholar
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.Google ScholarPubMed
Van Os, J, Kenis, G, Rutten, BPF (2010) The environment and schizophrenia. Nature 468, 203–212.Google Scholar
Van Os, J, Krabbendam, L, Myin-Germeys, I, Delespaul, P (2005). The schizophrenia envirome. Current Opinion in Psychiatry 18, 141–145.Google Scholar
Whitfield, JB, Zhu, G, Heath, AC, Martin, NG (2005). Choice of residential location: chance, family influences, or genes? Twin Research and Human Genetics 8, 22–26.Google Scholar
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, 1068–1087.Google Scholar
Yang, JA, Visscher, PM, Wray, NR (2010). Sporadic cases are the norm for complex disease. European Journal of Human Genetics 18, 1039–1043.Google Scholar
Supplementary material: PDF

Paksarian supplementary material

Appendix

Download Paksarian supplementary material(PDF)
PDF 137.4 KB