Advertisement

Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register

  • Author Footnotes
    1 RH and DH contributed equally to this work.
    Rikke Hilker
    Correspondence
    Address correspondence to Rikke Hilker, M.D., Ph.D., Center for Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital, Mental Health Centre Glostrup, Mental Health Services, Capital Region of Denmark, Nordre Ringvej 29-67, DK-2600, Glostrup, Denmark.
    Footnotes
    1 RH and DH contributed equally to this work.
    Affiliations
    CINS–Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark

    CNSR–Center for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Mental Health Services, Capital Region of Denmark, Glostrup, Denmark

    Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author
  • Author Footnotes
    1 RH and DH contributed equally to this work.
    Dorte Helenius
    Footnotes
    1 RH and DH contributed equally to this work.
    Affiliations
    Mental Health Centre Sct Hans, Mental Health Services, Capital Region of Denmark, Roskilde, Denmark

    iPSYCH–Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
    Search for articles by this author
  • Birgitte Fagerlund
    Affiliations
    CINS–Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark

    CNSR–Center for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Mental Health Services, Capital Region of Denmark, Glostrup, Denmark
    Search for articles by this author
  • Axel Skytthe
    Affiliations
    The Danish Twin Register, University of Southern Denmark, Odense, Denmark
    Search for articles by this author
  • Kaare Christensen
    Affiliations
    The Danish Twin Register, University of Southern Denmark, Odense, Denmark
    Search for articles by this author
  • Thomas M. Werge
    Affiliations
    CINS–Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark

    Mental Health Centre Sct Hans, Mental Health Services, Capital Region of Denmark, Roskilde, Denmark

    iPSYCH–Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
    Search for articles by this author
  • Merete Nordentoft
    Affiliations
    CINS–Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark

    Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    iPSYCH–Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark

    Mental Health Centre Copenhagen, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
    Search for articles by this author
  • Birte Glenthøj
    Affiliations
    CINS–Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup, Denmark

    CNSR–Center for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Mental Health Services, Capital Region of Denmark, Glostrup, Denmark

    Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author
  • Author Footnotes
    1 RH and DH contributed equally to this work.

      Abstract

      Background

      Twin studies have provided evidence that both genetic and environmental factors contribute to schizophrenia (SZ) risk. Heritability estimates of SZ in twin samples have varied methodologically. This study provides updated heritability estimates based on nationwide twin data and an improved statistical methodology.

      Methods

      Combining two nationwide registers, the Danish Twin Register and the Danish Psychiatric Research Register, we identified a sample of twins born between 1951 and 2000 (N = 31,524 twin pairs). Twins were followed until June 1, 2011. Liability threshold models adjusting for censoring with inverse probability weighting were used to estimate probandwise concordance rates and heritability of the diagnoses of SZ and SZ spectrum disorders.

      Results

      The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. We estimated the heritability of SZ to be 79%. When expanding illness outcome to include SZ spectrum disorders, the heritability estimate was almost similar (73%).

      Conclusions

      The key strength of this study is the application of a novel statistical method accounting for censoring in the follow-up period to a nationwide twin sample. The estimated 79% heritability of SZ is congruent with previous reports and indicates a substantial genetic risk. The high genetic risk also applies to a broader phenotype of SZ spectrum disorders. The low concordance rate of 33% in monozygotic twins demonstrates that illness vulnerability is not solely indicated by genetic factors.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • van Os J.
        • Kenis G.
        • Rutten B.P.F.
        The environment and schizophrenia.
        Nature. 2010; 468: 203-212
        • Sullivan P.F.
        • Daly M.J.
        • O’Donovan M.
        Genetic architectures of psychiatric disorders: The emerging picture and its implications.
        Nat Rev Genet. 2012; 13: 537-551
        • Boomsma D.
        • Busjahn A.
        • Peltonen L.
        Classical twin studies and beyond.
        Nat Rev Genet. 2002; 3: 872-882
        • Falconer D.S.
        • Mackay T.F.C.
        Introduction to Quantitative Genetics, 4th ed.
        Longman, Burnt Mill, England1996
        • Rijsdijk F.V.
        • Sham P.C.
        Analytic approaches to twin data using structural equation models.
        Brief Bioinform. 2002; 3: 119-133
        • Visscher P.M.
        • Hill W.G.
        • Wray N.R.
        Heritability in the genomics era—Concepts and misconceptions.
        Nat Rev Genet. 2008; 9: 255-266
        • Holst K.K.
        • Scheike T.H.
        • Hjelmborg J.B.
        The liability threshold model for censored twin data.
        Comput Stat Data Anal. 2016; 93: 324-335
        • Cardno A.G.
        • Gottesman II,
        Twin studies of schizophrenia: From bow-and-arrow concordances to star wars Mx and functional genomics.
        Am J Med Genet. 2000; 97: 12-17
        • Sullivan P.F.
        • Kendler K.S.
        • Neale M.C.
        Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies.
        Arch Gen Psychiatry. 2003; 60: 1187-1192
        • Cannon T.D.
        • Kaprio J.
        • Lönnqvist J.
        • Huttunen M.
        • Koskenvuo M.
        The genetic epidemiology of schizophrenia in a Finnish twin cohort.
        Arch Gen Psychiatry. 1998; 55: 67-74
        • Prescott C.A.
        • Kuhn J.W.
        • Pedersen N.L.
        Twin pair resemblance for psychiatric hospitalization in the Swedish Twin Registry: A 32-year follow-up study of 29,602 twin pairs.
        Behav Genet. 2007; 37: 547-558
        • Nordentoft M.
        • Wahlbeck K.
        • Hällgren J.
        • Westman J.
        • Ösby U.
        • Alinaghizadeh H.
        • et al.
        Excess mortality, causes of death and life expectancy in 270,770 patients with recent onset of mental disorders in Denmark, Finland and Sweden.
        PLoS One. 2013; 8e55176
        • Wahlbeck K.
        • Westman J.
        • Nordentoft M.
        • Gissler M.
        • Laursen T.M.
        Outcomes of Nordic mental health systems: Life expectancy of patients with mental disorders.
        Br J Psychiatry. 2011; 199: 453-458
        • Scheike T.H.
        • Holst K.K.
        • Hjelmborg J.B.
        Estimating heritability for cause specific mortality based on twin studies.
        Lifetime Data Anal. 2014; 20: 210-233
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Ripke S.
        • O’Dushlaine C.
        • Chambert K.
        • Moran J.L.
        • Kähler A.K.
        • Akterin S.
        • et al.
        Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
        Nat Genet. 2013; 45: 1150-1159
        • Haque F.N.
        • Gottesman II,
        • Wong A.H.C.
        Not really identical: Epigenetic differences in monozygotic twins and implications for twin studies in psychiatry.
        Am J Med Genet C Semin Med Genet. 2009; 151C: 136-141
        • Eichler E.E.
        • Flint J.
        • Gibson G.
        • Kong A.
        • Leal S.M.
        • Moore J.H.
        • et al.
        Missing heritability and strategies for finding the underlying causes of complex disease.
        Nat Rev Genet. 2010; 11: 446-450
        • Pedersen C.B.
        • Gøtzsche H.
        • Møller J.O.
        • Mortensen P.B.
        The Danish Civil Registration System. A cohort of eight million persons.
        Dan Med Bull. 2006; 53: 441-449
        • Skytthe A.
        • Kyvik K.O.
        • Holm N.V.
        • Christensen K.
        The Danish Twin Registry.
        Scand J Public Health. 2011; 39: 75-78
        • Mors O.
        • Perto G.P.
        • Mortensen P.B.
        The Danish Psychiatric Central Research Register.
        Scand J Public Health. 2011; 39: 54-57
        • World Health Organization
        Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death, Revision 8.
        World Health Organization, Geneva, Switzerland1967
        • World Health Organization
        The ICD-10 Classification of Mental and Behavioural Disorders. Clinical Descriptions and Diagnostic Guidelines.
        World Health Organization, Geneva, Switzerland1992
        • McGue M.
        When assessing twin concordance, use the probandwise not the pairwise rate.
        Schizophr Bull. 1992; 18: 171-176
        • Neale M.C.
        • Cardon L.R.
        Methodology for Genetic Studies of Twins and Families.
        Kluwer, Dordrecht1992
        • R Development Core Team
        R: A language and environment for statistical computing.
        R Foundation for Statistical Computing, Vienna, Austria2008 (ISBN 3-900051-07-0, URL)
        • Cardno A.G.
        • Marshall E.J.
        • Coid B.
        • Macdonald A.M.
        • Ribchester T.R.
        • Davies N.J.
        • et al.
        Heritability estimates for psychotic disorders: The Maudsley twin psychosis series.
        Arch Gen Psychiatry. 1996; 56: 162-168
        • Pedersen C.B.
        • Mors O.
        • Bertelsen A.
        • Waltoft B.L.
        • Agerbo E.
        • McGrath J.J.
        • et al.
        A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders.
        JAMA Psychiatry. 2014; 71: 573-581
        • van der Werf M.
        • Hanssen M.
        • Köhler S.
        • Verkaaik M.
        • Verhey F.R.
        • van Winkel R.
        • et al.
        Systematic review and collaborative recalculation of 133,693 incident cases of schizophrenia.
        Psychol Med. 2014; 44: 9-16
        • Thorup A.
        • Waltoft B.L.
        • Pedersen C.B.
        • Mortensen P.B.
        • Nordentoft M.
        Young males have a higher risk of developing schizophrenia: A Danish register study.
        Psychol Med. 2007; 37: 479-484
        • Mortensen P.B.
        • Pedersen M.G.
        • Pedersen C.B.
        Psychiatric family history and schizophrenia risk in Denmark: Which mental disorders are relevant?.
        Psychol Med. 2010; 40: 201-210
        • Uher R.
        Gene-environment interactions in severe mental illness.
        Front Psychiatry. 2014; 5: 48
        • van Dongen J.
        • Slagboom P.E.
        • Draisma H.H.M.
        • Martin N.G.
        • Boomsma D.I.
        The continuing value of twin studies in the omics era.
        Nat Rev Genet. 2012; 13: 640-653
        • Tenesa A.
        • Haley C.S.
        The heritability of human disease: Estimation, uses and abuses.
        Nat Rev Genet. 2013; 14: 139-149
        • Kendler K.S.
        Overview: A current perspective on twin studies of schizophrenia.
        Am J Psychiatry. 1983; 140: 1413-1425
        • Kendler K.S.
        • Robinette C.D.
        Schizophrenia in the National Academy of Sciences-National Research Council Twin Registry: A 16-year update.
        Am J Psychiatry. 1983; 140: 1551-1563
        • Fischer M.
        Genetic and environmental factors in schizophrenia. A study of schizophrenic twins and their families.
        Acta Psychiatr Scand Suppl. 1973; 238: 9-142
        • Walker E.
        • Downey G.
        • Caspi A.
        Twin studies of psychopathology: Why do the concordance rates vary?.
        Schizophr Res. 1991; 5: 211-221
        • Gottesman II,
        • Bertelsen A.
        Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer’s Danish identical and fraternal discordant twins.
        Arch Gen Psychiatry. 1989; 46: 867-872
        • Wray N.R.
        • Lee S.H.
        • Mehta D.
        • Vinkhuyzen A.A.
        • Dudbridge F.
        • Middeldorp C.M.
        Research review: Polygenic methods and their application to psychiatric traits.
        J Child Psychol Psychiatry. 2014; 55: 1068-1087
        • Uggerby P.
        • Østergaard S.D.
        • Røge R.
        • Correll C.U.
        • Nielsen J.
        The validity of the schizophrenia diagnosis in the Danish Psychiatric Central Research Register is good.
        Dan Med J. 2013; 60: A4578
        • Christensen K.
        • Mcgue M.
        Commentary: Twins, worms and life course epidemiology.
        Int J Epidemiol. 2012; 41: 1010-1011