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Cited by 2,125Schizophrenia research and treatmentBipolar Disorder and TreatmentGenetic Associations and Epidemiology

Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study

Open access
Lichtenstein, Paul, Yip, Benjamin H, Björk, Camilla, Pawitan, Yudi, Cannon, Tyrone D, Sullivan, Patrick F, Hultman, Christina M·2009·The Lancet
DOI 10.1016/s0140-6736(09)60072-6PMC PMC3879718
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Abstract

Background Whether schizophrenia and bipolar disorder are the clinical outcomes of discrete or shared causative processes is much debated in psychiatry. We aimed to assess genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and their comorbidity.Methods We linked the multi-generation register, which contains information about all children and their parents in Sweden, and the hospital discharge register, which includes all public psychiatric inpatient admissions in Sweden. We identified 9 009 202 unique individuals in more than 2 million nuclear families between 1973 and 2004. Risks for schizophrenia, bipolar disorder, and their comorbidity were assessed for biological and adoptive parents, offspring, full-siblings and half-siblings of probands with one of the diseases. We used a multivariate generalised linear mixed model for analysis of genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and the comorbidity.Findings First-degree relatives of probands with either schizophrenia (n=35 985) or bipolar disorder (n=40 487) were at increased risk of these disorders. Half-siblings had a significantly increased risk (schizophrenia: relative risk [RR] 3.6, 95% CI 2.3-5.5 for maternal half-siblings, and 2.7, 1.9-3.8 for paternal half-siblings; bipolar disorder: 4.5, 2.7-7.4 for maternal half-siblings, and 2.4, 1.4-4.1 for paternal half-siblings), but substantially lower than that of the full-siblings (schizophrenia: 9.0, 8.5-11.6; bipolar disorder: 7.9, 7.1-8.8). When relatives of probands with bipolar disorder were analysed, increased risks for schizophrenia existed for all relationships, including adopted children to biological parents with bipolar disorder. Heritability for schizophrenia and bipolar disorder was 64% and 59%, respectively. Shared environmental effects were small but substantial (schizophrenia: 4.5%, 4.4%-7.4%; bipolar disorder: 3.4%, 2.3%-6.2%) for both disorders. The comorbidity between disorders was mainly (63%) due to additive genetic effects common to both disorders.Interpretation Similar to molecular genetic studies, we showed evidence that schizophrenia and bipolar disorder partly share a common genetic cause. These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities.

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  • Schizophrenia has a lifetime risk of about 0.7% and heritability of 60-80% despite reduced reproductive fecundity.

    “Schizophrenia is a psychiatric disorder with a lifetime risk of about 0.7%1 and a heritability of 60–80%2,3 despite greatly reduced reproductive fecundity4,5.”

    From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [3]

  • Profound comorbidity exists across diagnostic labels thought to separate internalizing and externalizing disorders, with high phenotypic correlations between diagnosis pairs.

    “Profound comorbidity exists across diagnostic labels thought to separate internalizing and externalizing disorders; such studies reveal high phenotypic correlations between diagnosis pairs (13,14).”

    From Methods and challenges for assessing heterogeneity (2020) · cites this paper as [13]

  • Earlier work has applied liability models with full siblings and cousins to estimate additive genetic, shared environmental, and nonshared environmental effects for other outcomes.

    “Liability models using full siblings and cousins to estimate A, C, and E have been used earlier and for other outcomes (eg, skin cancer, 18,19 M component on preterm birth 5 and preeclampsia, 20,21 and comorbidity of 2 diseases).22”

    From Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort (2019) · cites this paper as [20]

  • Estimates from two different methods indicated that the risk profile component for SCZ contributes between a quarter and a third of the overall variance in liability to SCZ, a substantial fraction of the 65-81% heritability of SCZ.

    “Finally, estimates from two different methods indicated that the risk profile component for SCZ contributes between a quarter and a third of the overall variance in liability to SCZ, 69,130 a substantial fraction of the 65–81% heritability of SCZ. 179,180”

    From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [180]

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Authors
Lichtenstein, P., Yip, B. H., Björk, C., Pawitan, Y., Cannon, T. D., Sullivan, P. F., & Hultman, C. M.
Affiliations
  • Karolinska Institutet (SE)
  • University of California, Los Angeles (US)
  • University of North Carolina at Chapel Hill (US)
  • Uppsala University (SE)
Corresponding author
Lichtenstein, Paul
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2009-01
Volume
373
Issue
9659
Pages
234-239
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(09)60072-6
PMC
PMC3879718
OpenAlex
W2019465651
Cited by
2,125
References
30
Citations by year
2026: 39 · 2025: 81 · 2024: 82 · 2023: 79 · 2022: 117 · 2021: 122 · 2020: 138 · 2019: 143 · 2018: 127 · 2017: 158 · 2016: 154 · 2015: 146 · 2014: 152 · 2013: 147 · 2012: 156
FWCI
89.80
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Forskningsrådet för Arbetsliv och Socialvetenskap
  • National Institute of Mental Health (R01MH077139)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
schizophrenia, bipolar disorder, genetic comorbidity, heritability, shared environmental effects, half-siblings, full siblings, adopted children, nuclear family, additive genetic effects, disease classification, register linkage, psychiatric hospital admissions
MeSH terms
Bipolar Disorder, Environment, Family, Female, Genetics, Population, Humans, Male, Models, Genetic, Registries, Schizophrenia, Sweden, Comorbidity

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