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Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009 Jan 17 ; 373(9659):234-9. Pubmed Abstract

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

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 28 January 2009
Posted 29 January 2009
  I recommend this paper

This is a very interesting analysis and the largest and most definitive study to date. The results make clear that

1. some genetic effects are shared between BPD and schizophrenia;
2. some genetic effects are unique;
3. some environmental effects are shared;
4. some environmental effects are unique.

What is not known is which G or E effects validate diagnostic class. And whether all the effects are small, and apply to subgroups, and, therefore, may be more useful in resolving syndrome status than suggesting BPD and schizophrenia are one disease. The one-disease-or-two debate only has meaning if there are two diseases at most. More likely, we have two syndromes with some overlapping subjects, some overlapping psychopathology, some overlapping phenotypes.

The key question is whether to have the two syndromes as the unit of analysis for most studies. This can lead to new information on unique and shared effects, but the heterogeneity of the syndromes will confound this approach.

An alternative approach is the "domains of pathology" approach, which presumes that shared features related to psychopathology common in both syndromes (e.g., depression, reality distortion, cognition impairment) and unique features may relate to psychopathology usually not shared across the syndromes (e.g., avolition in schizophrenia, episodic mood pattern in BPD, differential developmental pathways, overall illness pattern, phenomenology of thought disorder). Domains of pathology also permit within syndrome studies (e.g., BPD with and without psychosis, deficit versus non-deficit schizophrenia).

References:

Strauss JS, Carpenter WT, Bartko JJ. The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull. 1974 Jan 1;:61-9. Abstract

Carpenter WT, Heinrichs DW, Wagman AM. Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988 May 1;145(5):578-83. Abstract

Carpenter WT, Buchanan RW, Kirkpatrick B, Tamminga C, Wood F. Strong inference, theory testing, and the neuroanatomy of schizophrenia. Arch Gen Psychiatry. 1993 Oct 1;50(10):825-31. Abstract

Buchanan RW, Carpenter WT. Domains of psychopathology: an approach to the reduction of heterogeneity in schizophrenia. J Nerv Ment Dis. 1994 Apr 1;182(4):193-204. Abstract

View all comments by William CarpenterComment by:  Alastair Cardno
Submitted 7 April 2009
Posted 7 April 2009
  I recommend the Primary Papers

The results of the family/adoption study by Lichtenstein et al. (2009) and our twin study (Cardno et al., 2002) are remarkably similar. Using a non-hierarchical diagnostic approach, the genetic correlation between schizophrenia and bipolar/mania was 0.60 in the family/twin study and 0.68 in the twin study. The heritability estimates were somewhat lower in the family/adoption (~60 percent) than twin study (~80 percent), but can still be said to be substantial and similar for both disorders.

When we adopted a hierarchical approach, with schizophrenia above mania, we found no monozygotic twin pairs where one twin had schizophrenia and the other had bipolar/mania, but with their considerably larger sample, Lichtenstein et al. (2009) were able to confirm a significantly elevated risk for bipolar disorder in siblings of probands with schizophrenia (RR = 2.7), even when individuals with co-occurrence of both disorders were excluded.

I think there is a potentially interesting link between the family/adoption and twin studies focusing mainly on non-hierarchical diagnoses: Owen and Craddock’s (2009) commentary on the family/adoption study, where they advocate a dimensional approach, and Will Carpenter’s SRF comment regarding the value of domains of psychopathology. The non-hierarchical approach (where individuals can have a diagnosis of both schizophrenia and bipolar disorder during their lifetime) could be viewed as a form of dimensional/domains of psychopathology approach, with schizophrenia and bipolar disorder each having a dimension of liability, and there is now evidence from family, twin, and adoption analyses that these dimensions are correlated, i.e., that there is some overlap in etiological influences.

If schizophrenia and bipolar disorder share some causal factors in common, what might be the implications for the unresolved status of schizoaffective disorder? Our twin study suggested that the genetic (but not environmental) liability to schizoaffective disorder is entirely shared with schizophrenia and mania, defined non-hierarchically (Cardno et al., 2002). If so, and if schizophrenia and bipolar disorder share some genetic susceptibility loci in common, while other loci are not shared, then risk of schizoaffective disorder (or perhaps the bipolar subtype) could be elevated either by the coincidental co-occurrence of non-shared susceptibility loci, or by the occurrence of loci that are common to both disorders.

In this case, any loci that influence risk of schizoaffective disorder (bipolar subtype?) should also increase risk of schizophrenia and/or bipolar disorder, and this model would be refuted if any relatively specific susceptibility loci for schizoaffective disorder were confidently identified.

Some further outstanding issues:



References:

Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. American Journal of Psychiatry 2002;159:539-545. Abstract

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234-9. Abstract

Owen MJ, Craddock N. Diagnosis of functional psychoses: time to face the future. Lancet 2009;373:190-191. Abstract

View all comments by Alastair Cardno