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Risk of schizophrenia in relation to parental origin and genome-wide divergence

  • C. B. Pedersen (a1), D. Demontis (a2), M. S. Pedersen (a1), E. Agerbo (a1), P. B. Mortensen (a1), A. D. Børglum (a2) (a3), D. M. Hougaard (a4), M. V. Hollegaard (a4), O. Mors (a3) and E. Cantor-Graae (a5)...

Second-generation immigrants have an increased risk of schizophrenia, a finding that still lacks a satisfactory explanation. Various operational definitions of second-generation immigrants have been used, including foreign parental country of birth. However, with increasing global migration, it is not clear that parental country of birth necessarily is informative with regard to ethnicity. We compare two independently collected measures of parental foreign ethnicity, parental foreign country of birth versus genetic divergence, based on genome-wide genotypic data, to access which measure most efficiently captures the increased risk of schizophrenia among second-generation immigrants residing in Denmark.


A case–control study covering all children born in Denmark since 1981 included 892 cases of schizophrenia and 883 matched controls. Genetic divergence was assessed using principal component analyses of the genotypic data. Independently, parental foreign country of birth was assessed using information recorded prospectively in the Danish Civil Registration System. We compared incidence rate ratios of schizophrenia associated with these two independently collected measures of parental foreign ethnicity.


People with foreign-born parents had a significantly increased risk of schizophrenia [relative risk (RR) 1.94 (95% confidence intervals (CI) 1.41–2.65)]. Genetically divergent persons also had a significant increased risk [RR 2.43 (95% CI 1.55–3.82)]. Mutual adjustment of parental foreign country of birth and genetic divergence showed no difference between these measures with regard to their potential impact on the results.


In terms of RR of schizophrenia, genetic divergence and parental foreign country of birth are interchangeable entities, and both entities have validity with regard to identifying second-generation immigrants.

Corresponding author
*Address for correspondence: Dr C. B. Pedersen, National Centre for Register-based Research, Aarhus University, Taasingegade 1, 8000 Aarhus C, Denmark. (Email:
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Andersen PK, Borgan Ø, Gill RD, Keiding N (1997). Statistical Models Based on Counting Processes. Springer: New York.
Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB (2003). Parental age and risk of schizophrenia: a case–control study. Archives of General Psychiatry 60, 673678.
Cantor-Graae E, Pedersen CB (2007). Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study. Psychological Medicine 37, 485494.
Cantor-Graae E, Selten JP (2005). Schizophrenia and migration: a meta-analysis and review. American Journal of Psychiatry 162, 1224.
Clayton D, Hills M (1993). Statistical Models in Epidemiology. Oxford University Press: Oxford, New York, Tokyo.
Coid JW, Kirkbride JB, Barker D, Cowden F, Stamps R, Yang M, Jones PB (2008). Raised incidence rates of all psychoses among migrant groups: findings from the East London first episode psychosis study. Archives of General Psychiatry 65, 12501258.
Corcoran C, Perrin M, Harlap S, Deutsch L, Fennig S, Manor O, Nahon D, Kimhy D, Malaspina D, Susser E (2009). Incidence of schizophrenia among second-generation immigrants in the Jerusalem Perinatal Cohort. Schizophrenia Bulletin 35, 596602.
Fearon P, Morgan C (2006). Environmental factors in schizophrenia: the role of migrant studies. Schizophrenia Bulletin 32, 405408.
Hollegaard MV, Grauholm J, Borglum A, Nyegaard M, Norgaard-Pedersen B, Orntoft T, Mortensen PB, Wiuf C, Mors O, Didriksen M, Thorsen P, Hougaard DM (2009). Genome-wide scans using archived neonatal dried blood spot samples. BMC Genomics 10, 297.
Hulshoff Pol HE, Hoek HW, Susser E, Brown AS, Dingemans A, Schnack HG, van Haren NE, Pereira Ramos LM, Gispen-de Wied CC, Kahn RS (2000). Prenatal exposure to famine and brain morphology in schizophrenia. American Journal of Psychiatry 157, 11701172.
Hunter-Zinck H, Musharoff S, Salit J, Al-Ali KA, Chouchane L, Gohar A, Matthews R, Butler MW, Fuller J, Hackett NR, Crystal RG, Clark AG (2010). Population genetic structure of the people of Qatar. American Journal of Human Genetics 87, 1725.
Jakobsen KD, Frederiksen JN, Hansen T, Jansson LB, Parnas J, Werge T (2005). Reliability of clinical ICD-10 schizophrenia diagnoses. Nordic Journal of Psychiatry 59, 209212.
Janssen I, Hanssen M, Bak M, Bijl RV, de Graaf R, Vollebergh W, McKenzie K, van Os J (2003). Discrimination and delusional ideation. British Journal of Psychiatry 182, 7176.
King G, Zeng L (2002). Estimating risk and rate levels, ratios and differences in case-control studies. Statistics in Medicine 21, 14091427.
McGrath J (1999). Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophrenia Research 40, 173177.
McVean G (2009). A genealogical interpretation of principal components analysis. PLoS Genetics 5, e1000686.
Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL, Hougaard D, Torrey EF, Yolken RH (2007). Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth. Biological Psychiatry 61, 688693.
Mortensen PB, Pedersen CB, Hougaard DM, Norgaard-Petersen B, Mors O, Borglum AD, Yolken RH (2010). A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring. Schizophrenia Research 122, 257263.
Munk-Jorgensen P, Mortensen PB (1997). The Danish Psychiatric Central Register. Danish Medical Bulletin 44, 8284.
Norgaard-Pedersen B, Hougaard DM (2007). Storage policies and use of the Danish Newborn Screening Biobank. Journal of Inherited Metabolic Disease 30, 530536.
Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, Nelson MR, Stephens M, Bustamante CD (2008). Genes mirror geography within Europe. Nature 456, 98–101.
Patterson N, Price AL, Reich D (2006). Population structure and eigenanalysis. PLoS Genetics 2, e190.
Pedersen CB (2006). No evidence of time trends in the urban-rural differences in schizophrenia risk among five million people born in Denmark from 1910 to 1986. Psychological Medicine 36, 211219.
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, Mortensen PB (2001). 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, Cantor-Graae E (2011). Do risk factors for schizophrenia predispose to emigration? Schizophrenia Research 127, 229234.
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.
Price AL, Zaitlen NA, Reich D, Patterson N (2010). New approaches to population stratification in genome-wide association studies. Nature Review Genetics 11, 459463.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics 81, 559575.
Royston P, Ambler G, Sauerbrei W (1999). The use of fractional polynomials to model continuous risk variables in epidemiology. International Journal of Epidemiology 28, 964974.
SAS Institute Inc. (2008). The PhReg procedure. In SAS/STAT 9.2 User's Guide. SAS Institute Inc.: Cary, NC.
SAS Institute Inc. (2009). SAS 9.2 Language Reference: Dictionary, 2nd edn. SAS Institute Inc.: Cary, NC.
Selten JP, Cantor-Graae E (2007). Hypothesis: social defeat is a risk factor for schizophrenia? British Journal of Psychiatry (Supplement) 51, s9–s12.
Sharpley M, Hutchinson G, McKenzie K, Murray RM (2001). Understanding the excess of psychosis among the African-Caribbean population in England. Review of current hypotheses. British Journal of Psychiatry Supplement 40, s60s68.
Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, Gorman JM (1996). Schizophrenia after prenatal famine. Further evidence. Archives of Geneneral Psychiatry 53, 2531.
Veling W, Susser E, van Os J, Mackenbach JP, Selten JP, Hoek HW (2008). Ethnic density of neighborhoods and incidence of psychotic disorders among immigrants. American Journal of Psychiatry 165, 6673.
Weiser M, Werbeloff N, Vishna T, Yoffe R, Lubin G, Shmushkevitch M, Davidson M (2008). Elaboration on immigration and risk for schizophrenia. Psychological Medicine 38, 11131119.
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Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
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