Elsevier

The Lancet

Volume 373, Issue 9659, 17–23 January 2009, Pages 234-239
The Lancet

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

https://doi.org/10.1016/S0140-6736(09)60072-6Get rights and content

Summary

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.

Funding

Swedish Council for Working Life and Social Research, and the Swedish Research Council.

Introduction

Opinions differ about whether schizophrenia and bipolar disorder have a common cause. Some think that schizophrenia and bipolar disorder are the clinical outcomes of entirely different processes, whereas others believe in identical processes. Several intermediate and more-complicated hypotheses can also be envisioned whereby, for example, a shared causative risk factor is responsible for part of each disorder. A common cause has been suggested by molecular genetic studies1 by the existence of an intermediate phenotype (schizoaffective disorder), which shares diagnostic features of both disorders, and by evidence that similar endophenotypes (eg, brain white-matter density)2 are associated with both disorders. However, evidence from genetic epidemiological studies is mixed partly because of small sample sizes.3, 4

Genome-wide linkage screenings have shown some overlap between schizophrenia and bipolar disorder.5, 6 One meta-analysis showed genomic regions in common,7 although a more inclusive meta-analysis suggested that no overlap of the highest-ranking regions for the two disorders existed;8, 9 a third meta-analysis with genotype data from individual studies did not show strong overlap.10 However, overlap can arise by chance. If we assume three 500-marker genome scans for schizophrenia and three for bipolar disorder, with a simple simulation model (α=0·05, 10 000 simulations) with no true genetic effects, the absence of positional overlap between any schizophrenia scan and any bipolar disorder scan would be uncommon (7%), one overlap would happen frequently (18%), and multiple overlaps would predominate (75%). Therefore, because there are 20 schizophrenia and 18 bipolar disorder genome-wide linkage scans,8, 9 substantial overlap across studies is to be expected purely by chance. An additional difficulty is that individuals with schizoaffective disorder are generally classified as affected in genetic studies of each syndrome.8, 9

Some workers have investigated the genetic association of markers in candidate genes in both schizophrenia and bipolar disorder.11, 12, 13 These studies provide evidence for an overlap in genetic susceptibility between the two disorders, and for the possibility of specific associations between genotype and type of pathology,1 although interpretations should be drawn with caution.14

Studies that are based on diagnostic resemblance in familial relationships can be helpful to understand the sources of overlap between two disorders. One twin study15 is usually cited as supporting the overlap between schizophrenia and bipolar disorder, although its conclusions are qualified by a small sample size and assessment of mania, rather than bipolar disorder per se. A small Finnish study16 of 26 twins with bipolar disorder did not identify any co-twin with schizophrenia. High-quality family studies have suggested that schizophrenia and bipolar disorder do not overlap.3, 4 One study5 stated “there is no increased risk for bipolar disorder among first-degree relatives of schizophrenia probands…nor is there increased risk for schizophrenia among first-degree relatives of bipolar disorder probands”. However, in a large population-based study in Denmark,17 risk of bipolar disorder was associated with a history of schizophrenia in parents and siblings.

Because the relation between schizophrenia and bipolar disorder is unclear, we have used population-based registries that contain the entire Swedish population to assess the degree of genetic overlap between these two disorders.

Section snippets

National registers

We linked two Swedish national registers, using the unique, individual Swedish national registration number, which was introduced in 1947 and is assigned at birth.

The multi-generation register contains information about first-degree relatives.18 This register includes entries for an index person along with their biological and adoptive parents. To be in the register, an index person had to be registered in Sweden between Jan 1, 1961, and Dec 31, 2002, and to have been born between Jan 1, 1932,

Results

We identified 9 009 202 unique individuals of known parentage, for whom both parents were alive and living in Sweden after 1973. 35 985 individuals met the criteria for schizophrenia and 40 487 individuals for bipolar disorder. Of those with schizophrenia, 2543 also had bipolar disorder (relative risk [RR] 16·4, 95% CI 15·1–17·7). We have previously shown the recurrence risks for schizophrenia.22 Table 2 presents these results for parent–offspring and sibling relationships, and extends our

Discussion

In this study of more than 2 million Swedish families, we found evidence of a substantial genetic association between schizophrenia and bipolar disorder. All classes of biological relatives of probands with bipolar disorder had increased risk for schizophrenia, and the genetic correlation (ie, the correlation between the genetic effects that determine the liabilities for the two disorders) was 0·60. Furthermore, adopted children whose biological parents had one of these disorders had

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