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Cytogenetics Offer Up Another Schizophrenia, Bipolar Candidate Gene

4 January 2010. The membrane lipid transporter gene ABCA13 is identified as a candidate susceptibility factor for schizophrenia and bipolar disorder in a Scottish cohort, according to data from a team led by Ben Pickard, now of the University of Strathclyde in Glasgow, United Kingdom. The study, published in the December 11 issue of the American Journal of Human Genetics, highlights the genetic overlap between major psychiatric disorders by identifying for the first time, the authors write, multiple and combined coding variants in a single gene associated with these disorders.

Pickard and co-first author Helen Knight, now at the University of Cambridge, United Kingdom, led a multi-institution collaboration centered at Edinburgh University that first identified cytogenetic disruption of the ABCA13 gene in a person with schizophrenia. Resequencing of key coding regions in a sample of patients and controls revealed 10 rare variants, which were significantly enriched in schizophrenia and bipolar patients in a much larger sample.

No longer so separate
Historically, schizophrenia and mood disorders have been defined as separate mental disorders. However, recent molecular genetic studies suggest a common origin, and results from a large epidemiological study of nine million Swedes over a 30-year period also support a shared genetic risk for the disorders (see SRF related news story). Lichtenstein and colleagues at the Karolinska Institute in Stockholm found that first-degree relatives of people with schizophrenia are at higher risk for bipolar disorder, and vice versa (see also SRF live discussion).

“Recent genomewide association studies that probe common variation at the whole genome scale in large case-control cohorts have found, and sometimes replicated, significant associations of a number of candidate genes with schizophrenia and bipolar disorder and have found substantial overlap of risk factors between these two illnesses,” Knight and colleagues write, citing a number of studies. At the November 2009 World Congress of Psychiatric Genetics, the Psychiatric GWAS Conortium (PGC) working group discussed efforts to examine common variants that play a role in individual disorders as well as to elucidate the shared genetic risk for disorders such as schizophrenia and bipolar disorder (see SRF related news story).

In addition to common polygenic variation, rare copy number variants (CNVs) may also contribute to overlapping disease risk (see SRF related news story). The study of gross cytogenetic abnormalities (visible to the trained eye under a microscope; see SRF related news story), likewise, can be informative. Interestingly, the ABCA13 findings come from the same group in Scotland, using the same old-fashioned karyotyping as a starting point, that first reported DISC1, the most promising gene candidate to date for schizophrenia and mood disorders.

In the current study, Knight and colleagues identified a schizophrenia patient with a pericentric inversion of chromosome 7 coupled with a translocation between chromosomes 7 and 8. The affected gene belongs to the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of genes, which code for molecules that transport a variety of substrates across membranes. The authors restricted the resequencing of ABCA13, a very large gene, to selected exons (two transmembrane domains and two cytoplasmic nucleotide binding domains and a hydrophobic membrane-dipping region) in 100 individuals with schizophrenia and 100 controls, and identified 10 non-synonymous rare coding variants.

A new, larger “test” sample of individuals with schizophrenia, bipolar disorder, depression, and controls was then evaluated for variant frequencies. Analysis of affected and unaffected family members of those with mutations in this “test” sample was also undertaken. When taken together, the 10 ABCA13 coding variants were significantly associated with schizophrenia and bipolar disorder. "The population attributable risk of the 10 rare non-synonymous mutations was 2.2 percent for schizophrenia and 4.0 percent for bipolar disorder, suggesting that this gene may have an important role in a subgroup of patients and an influence that crosses traditional diagnostic boundaries," the authors write.

Interestingly, additive effects on risk was suggested by five cases of compound heterozygosity and one case of homozygosity, whereas all controls with risk variants were monoallelic. Five cases possessed more than one rare variant simultaneously, and one case showed that a single rare variant damaged both copies of the gene. In contrast, not a single control possessed more than one copy of a rare variant. This observation leads the authors to suggest that additive and interactive combinations of mutations may contribute to these complex disorders.

Lastly, the authors demonstrated that ABCA13 protein is expressed in mouse and human hippocampus and cortex, brain regions relevant in schizophrenia and bipolar disorder.

In an e-mail to SRF, Pickard speculates, “ABCA13 is involved in the metabolism of an as yet unknown lipid, and this lipid may be important in aspects of neuronal function or development such as neurite outgrowth. There is some precedent to this line of enquiry; a closely related gene, ABCA12, which is mutated in a skin disorder called Harlequin Ichthyosis, results in a failure of the skin cells to secrete a lipid called ceramide, causing a frequently fatal skin malformation in neonates. Something equivalent may be happening in the brains of those with ABCA13 mutations. While this is not in line with established models of psychiatric illness (e.g., dopamine/glutamate hypotheses), the fact that we see the same ABCA13 mutations spanning diagnostic boundaries suggests that it must be regulating a fairly fundamental process.”—J. Meggin Hollister.

Reference:
Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, Condie A, White A, Hawkins W, McGhee K, van Beck M, MacIntyre DJ, Starr JM, Deary IJ, Visscher PM, Porteous DJ, Cannon RE, St Clair D, Muir WJ, Blackwood DH. A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum Genet. 2009 Dec;85(6):833-46. Abstract

Comments on Related News


Related News: Large Family Study Links Genetics of Schizophrenia, Bipolar Disorder

Comment 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

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Katie Rodriguez
Submitted 7 November 2009
Posted 7 November 2009

If schizophrenia and autism are on a spectrum, how can there be people who are both autistic and schizophrenic? I know of a few people who suffer from both diseases.

View all comments by Katie Rodriguez

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Bernard Crespi
Submitted 12 November 2009
Posted 12 November 2009

One Hundred Years of Insanity: The Relationship Between Schizophrenia and Autism
The great Colombian author Gabriel García Márquez reified the cyclical nature of history in his Nobel Prize-winning 1967 book, One Hundred Years of Solitude. Eugen Bleuler’s less-famous book Dementia Præcox or the Group of Schizophrenias, originally published in 1911, saw first use of the term “autism,” a form of solitude manifest as withdrawal from reality in schizophrenia. This neologism, about to celebrate its centenary, epitomizes an astonishing cycle of reification and change in nosology, a cycle only now coming into clear view as molecular-genetic data confront the traditional, age-old categories of psychiatric classification.

The term autism was, of course, redefined by Leo Kanner (1943) for a childhood psychiatric condition first considered as a subset of schizophrenia, then regarded as quite distinct (Rutter, 1972) or even opposite to it (Rimland, 1964; Crespi and Badcock, 2008), and most recently seen by some researchers as returning to its original Bluelerian incarnation (e.g., Carroll and Owen, 2009). An outstanding new paper by McCarthy et al. (2009), demonstrating that duplications of the CNV locus 16p11.2 are strongly associated with increased risk of schizophrenia, has brought this question to the forefront of psychiatric inquiry, because deletions of this same CNV are one of the most striking recently-characterized risk factors for autism. Additional CNVs, such as those at 1q21.1 and 22q11.21 have also been associated with autism and schizophrenia in one or more studies (e.g., Mefford et al., 2008; Crespi et al., 2009; Glessner et al., 2009), which has led some authors to infer that since an overlapping set of loci mediates risk of both conditions, autism and schizophrenia must be more similar than previously conceived (e.g., Carroll and Owen, 2009; Guilmatre et al., 2009). Similar considerations apply to several genes, such as CNTNAP2 and NRXN1, various disruptions of which have likewise been linked with both conditions (Iossifov et al., 2008; Kirov et al., 2008; Burbach and van der Zwaag, 2009).

So does this plethora of new molecular-genetic data imply that Blueler was indeed correct, if not prescient, that autism and schizophrenia are manifestations of similar disease processes? The answer may appear tantalizingly close, but will likely remain inaccessible without explicit consideration of alternative hypotheses and targeted tests of their differentiating predictions. This approach is simply Platt’s (1964) classic method of strong inference, which has propelled molecular biology so far and fast but left psychiatry largely by the wayside (Cannon, 2009). The alternative hypotheses in this case are clear: with regard to causation from specific genetic and genomic risk factors, autism and schizophrenia are either: 1) independent and discrete, 2) partially yet broadly overlapping, 3) subsumed with autism as a subset of schizophrenia, or 4) diametrically opposite, with normality in the centre. CNVs are especially useful for testing among such alternative hypotheses, because they naturally involve highly-penetrant perturbations in two opposite directions, due to deletions vs duplications of more or less the same genomic regions. Hypotheses 2), 3) and 4) thus predict that autism and schizophrenia should share CNV risk loci, but 2) and 3) predict specific rearrangements (deletions, duplications, or both) shared across both conditions; by contrast, hypothesis (4) predicts that, as highlighted by McCarthy et al. (2009), reciprocal CNVs at the same locus should mediate risk of autism versus schizophrenia. This general approach was pioneered by Craddock et al. (2005, 2009), in their discussion of explicit alternative hypotheses for the relationship between schizophrenia and bipolar disorder, which are now known to share a notable suite of risk alleles.

A key assumption that underlies tests of hypotheses for the relationship between autism and schizophrenia is accuracy of diagnoses. For schizophrenia, this is seldom at issue. However, diagnoses of autism, or autism spectrum disorders such as PDD-NOS, are normally made at an age well before the first manifestations of schizophrenia in adolescence or early adulthood, which generates a risk for false-positive diagnoses of premorbidity to schizophrenia as autism or autism spectrum (e.g., Eliez, 2007). The tendencies for males to exhibit worse premorbidity to schizophrenia than females (Sobin et al., 2001; Tandon et al., 2009), for CNVs to exert severe effects on diverse aspects of early neurodevelopment (Shinawi et al., 2009), and for schizophrenia of earlier onset to exhibit a higher male sex-ratio bias and a stronger tendency to be associated with CNVs rather than other causes (Remschmidt et al., 1994; Rapoport et al., 2009), all suggest a high risk for false-positive diagnoses of autistic spectrum conditions in individuals with these genomic risk factors (Feinstein and Singh, 2007; Reaven et al., 2008; Sugihara et al., 2008; Starling and Dossetor, 2009). Possible evidence of such risk comes from diagnoses of autism spectrum conditions in children with deletions at 15q11.2, 15q13.3, and 22q11.21, and duplications of 16p11.2, CNVs for which schizophrenia risk has been well established from studies of adults (Antshel et al., 2007; Stefansson et al., 2008; Weiss et al., 2008; Ben-Shachar et al., 2009; Doornbos et al., 2009; McCarthy et al., 2009). By contrast, autism-associated CNVs, such as deletions at 16p11.2 (Kumar et al., 2008), or duplications at 22q11.21 (Glessner et al., 2009; Crespi et al., 2009) have seldom also been reported in individuals diagnosed with schizophrenia, which suggests that false-positive diagnoses of schizophrenia as autism are uncommon.

Differentiating between a hypothesis of false-positive diagnoses of premorbidity to schizophrenia as autism, compared to a hypothesis of specific deletions or duplications shared between autism and schizophrenia, requires some combination of longitudinal studies, judicious use of endophenotypes, and adoption of relatively new diagnostic categories such as multiple complex developmental disorder (Sprong et al., 2008). Moreover, to the degree that such false positives are not uncommon, and autism and schizophrenia are underlain by diametric genetically based risk factors, inclusion of children premorbid for schizophrenia in studies on the genetic bases of autism will substantially dilute the probability of detecting significant results.

Ultimately, robust evaluation of alternative hypotheses for the relationship of autism with schizophrenia will require evidence from studies of common and rare SNP variants as well as CNVs, in-depth analyses of the neurodevelopmental and neuronal-function effects of different alterations to genes such as NRXN1, CNTNAP2, and SHANK3, and integrative data from diverse disciplines other than genetics, especially the neurosciences and psychology. Unless such interdisciplinary studies are deployed—in hypothesis-testing frameworks that use strong inference—we should expect to remain, as penned by García Márquez, in “permanent alternation between excitement and disappointment, doubt and revelation, to such an extreme that no one knows for certain where the limits of reality lay”—for yet another 100 years.

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View all comments by Bernard Crespi

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Suzanna Russell-SmithDonna BaylissMurray Maybery
Submitted 9 February 2010
Posted 10 February 2010

The Diametric Opposition of Autism and Psychosis: Support From a Study of Cognition
As has been noted previously, Crespi and Badcock’s (2008) theory that autism and schizophrenia are diametrically opposed disorders is certainly a novel and somewhat controversial one. In his recent blog on Psychology Today, Badcock states that the theory stands on two completely different foundations: one in evolution and genetics, and one in psychiatry and cognitive science (Badcock, 2010). While most of the comments posted before ours have addressed the relationship between autism and schizophrenia from a genetic perspective, coming from a psychology background, we note that it is the aspects of Crespi and Badcock’s theory that relate to cognition which have particularly caught our attention. While we can therefore contribute little to the discussion of a relationship between autism and schizophrenia from a genetic standpoint, we present the findings from our recent study (Russell-Smith et al., 2010), which provided the first test of Crespi and Badcock’s claim that autism and psychosis are at opposite ends of the cognitive spectrum.

In placing autism and psychosis at opposite ends of the cognitive spectrum, Crespi and Badcock (2008) propose that autistic and positive schizophrenia traits contrastingly affect preference for local versus global processing, with individuals with autism displaying a preference for local processing and individuals with positive schizophrenia displaying a preference for global processing. That is, these authors claim that while individuals with autism show a tendency to focus on detail or process features in their isolation, individuals with positive schizophrenia show a tendency to look at the bigger picture or process features as an integrated whole. Importantly, since Crespi and Badcock argue for a continuum stretching all the way from autism to psychosis, the same diametric pattern of cognition should be seen in individuals who display only mild variants of autistic and positive schizophrenia traits. This includes typical individuals who score highly on measures such as the Autism Spectrum Quotient (AQ; Baron-Cohen et al., 2001) and the Unusual Experiences subscale of the Oxford-Liverpool Inventory of Experiences (O-LIFE:UE; Mason et al., 2005). These are both reliable and commonly used measures which have been specifically designed to assess the levels of “autistic-like” traits and positive schizotypy traits in typical individuals. Since Crespi and Badcock actually argue their theory is best evaluated with reference to individuals with milder traits of autism and positive schizophrenia, it is with these populations that we investigated their claims.

A task often used to determine whether an individual has a preference for local over global processing is the Embedded Figures Test (EFT; Witkin et al., 1971), which requires individuals to detect hidden shapes within complex figures. As the test requires one to resist experiencing an integrated visual stimulus or gestalt in favor of seeing single elements, it is argued that a local processing style aids successful (i.e., faster) completion of this task (Bolte et al., 2007). Accordingly, from Crespi and Badcock’s (2008) theory, one would expect that relative to individuals with low levels of these traits, individuals with high levels of autistic-like traits should perform better on the EFT, while individuals with positive schizotypy traits should perform worse. To test this claim, our study obtained the AQ and O-LIFE:UE scores for 318 students completing psychology as part of a broader degree (e.g., a BSc or BA). Two pairs of groups (i.e., four groups in total), each consisting of 20 students, were then formed. One of these pairs consisted of High and Low AQ groups, which were selected such that they were separated substantially in their AQ scores but matched as closely as possible on their O-LIFE:UE scores. The other pair of groups, the High and Low O-LIFE:UE groups, were selected such that they were separated in their O-LIFE:UE scores, but matched as closely as possible on their AQ scores. The gender ratio was matched closely across the four groups.

To test the prediction that higher levels of autistic-like traits are associated with more skilled EFT performance, the High and Low AQ groups were compared in terms of their mean response time to accurately locate each of the embedded figures. Individuals in the High AQ group did display more skilled EFT performance than individuals in the Low AQ group, consistent with a greater preference for local over global processing in relation to higher levels of autistic-like traits (see also Almeida et al., 2010; Bolte and Poustka, 2007; Grinter et al., 2009; Grinter et al., 2009). We then compared EFT performance for the O-LIFE:UE groups to test the prediction that higher levels of positive schizotypy traits are associated with less skilled performance on this task. Consistent with a preference for global over local processing in relation to higher levels of positive schizotypy traits, individuals in the High O-LIFE:UE group displayed less skilled EFT performance than individuals in the Low O-LIFE:UE group. Therefore, results from both pairs of groups together provide support for Crespi and Badcock’s (2008) claim that autistic and positive schizophrenia traits are diametrically opposed with regard to their effect on local versus global processing.

However, the support our study offers for Crespi and Badcock’s (2008) theory was tempered slightly by our failure to find the expected contrasting patterns of non-verbal relative to verbal ability for our two pairs of groups. To display the expected patterns, relative to individuals with low levels of these traits, individuals with high levels of autistic-like traits should have displayed higher non-verbal ability relative to verbal ability, whereas individuals with high levels of positive schizotypy traits should have displayed lower non-verbal relative to verbal ability. While visual inspection of mean verbal and non-verbal scores for the O-LIFE:UE groups revealed a trend consistent with what would be expected based on Crespi and Badcock’s theory, none of the group differences was statistically significant. However, as we pointed out in our article, a study which offers a more complete assessment of this aspect of the theory is warranted. In particular, since the use of a student sample in our study no doubt led to a restriction in the range of IQ scores (especially with reference to verbal IQ), a test of community-based samples would be useful.

Therefore, while Crespi and Badcock’s (2008) theory has passed its first major test at the level of cognition, with our results indicating a contrasting effect of autistic-like and positive schizotypy traits with regard to preference for local versus global processing, further investigation of these authors’ theory at both the cognitive and genetic levels is required.

References:

Almeida, R., Dickinson, J., Maybery, M., Badcock, J., Badcock, D. A new step toward understanding Embedded Figures Test performance in the autism spectrum: The radial frequency search task. Neuropsychologia. 2010 Jan;48(2):374-81. Abstract

Badcock, C. (2010). Diametric cognition passes its first lab test. Psychology Today. Retrieved February 8, from http://www.psychologytoday.com/blog/the-imprinted-brain/201002/diametric-cognition-passes-its-first-lab-test.

Baron-Cohen, S., Wheelwright, S., Skinner, R., Martin, J., Clubley, E. (2001). The Autism-Spectrum Quotient (AQ): Evidence from Asperger Syndrome/High-Functioning Autism, males and females, scientists and mathematicians. Journal of Autism and Developmental Disorders, 31, 5-17. Abstract

Bolte, S., Holtmann, M., Poustka, F., Scheurich, A., Schmidt, L. (2007). Gestalt perception and local-global processing in High-Functioning Autism. Journal of Autism and Developmental Disorders, 37, 1493-1504. Abstract

Bolte, S., Poustka, F. (2006). The broader cognitive phenotype of autism in parents: How specific is the tendency for local processing and executive function. Journal of Child Psychology and Psychiatry, 47, 639-645. Abstract

Crespi, B., Badcock, C. (2008). Psychosis and autism as diametrical disorders of the social brain. Behavioral and Brain Sciences, 31, 241-261. Abstract

Grinter, E., Maybery, M., Van Beek, P., Pellicano, E., Badcock, J., Badcock, D. (2009). Global visual processing and self-rated autistic-like traits. Journal of Autism and Developmental Disorders, 39, 1278-1290. Abstract

Grinter, E., Van Beek, P., Maybery, M., Badcock, D. (2009). Brief Report: Visuospatial analysis and self-rated autistic-like traits. Journal of Autism and Developmental Disorders, 39, 670–677. Abstract

Mason, O., Linney, Y., Claridge, G. (2005). Short scales for measuring schizotypy. Schizophrenia Research, 78, 293-296. Abstract

Russell-Smith, S., Maybery, M., Bayliss, D. Are the autism and positive schizotypy spectra diametrically opposed in local versus global processing? Journal of Autism and Developmental Disorders. 2010 Jan 28. Abstract

Witkin, H., Oltman, P., Raskin, E., Karp, S. (1971). A manual for the Embedded Figures Test. Palo Alto, CA: Consulting Psychologists Press.

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Related News: With Two Affected Parents, Schizophrenia Risk in Offspring Skyrockets

Comment by:  Peter Propping
Submitted 16 March 2010
Posted 16 March 2010

The study by Gottesman et al. is extremely important. Its value derives from the fact that the incidences come from a registry-based ascertainment of cases and from a country with national health insurance. Thus, the usual selective influences on ascertainment can largely be excluded. The empirical risk figures derived from this dual-mating study are much higher than in offspring where only one parent was affected by either schizophrenia or bipolar disorder. In the present study, however, the risk figures were somewhat lower than reported in some earlier studies (conducted in Germany, the United States, and the United Kingdom), where the cases had been ascertained through clinical admissions (Kahn, 1923; Kallman, 1938; Schulz, 1940; Elsässer, 1952; Lewis, 1957; Gershon et al., 1982). The major explanation is likely to be the ascertainment bias in the earlier studies.

Interestingly, this study found somewhat higher risks for both schizophrenia and bipolar disorder in the offspring of matings where one parent had schizophrenia and the other bipolar disorder. This points to a genetic overlap between the predispositions to the two diseases. An overlap is also suggested by recent molecular studies (e.g., Steinberg et al., 2010). If a genetic association has been found with one of the two disorders, it should also be tested in the other disorder.

References:

Steinberg S, Mors O, Børglum AD, Gustafsson O, Werge T, Mortensen PB, Andreassen OA, Sigurdsson E, Thorgeirsson TE, Böttcher Y, Olason P, Ophoff RA, Cichon S, Gudjonsdottir IH, Pietiläinen OPH, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Athanasiu L, Suvisaari J, Lonnqvist J, Paunio T, Hartmann A, Jürgens G, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Breuer R, Möller H-J, Giegling I, Glenthøj B, Rasmussen HB, Mattheisen M, Bitter I, Réthelyi JM, Sigmundsson T, Fossdal R, Thorsteinsdottir U, Ruggeri M, Tosato S, Strengman E, GROUP, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Walshe M, Bramon E, Vassos E, Li T, Fraser G, Walker N, Toulopoulou T, Yoon J, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Jönsson EG, Terenius L, Agartz I, Petursson H, Nöthen MN, Rietschel M, Peltonen L, Rujescu D, Collier DA, Stefansson H, St Clair D, Stefansson K. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry. 2010 Jan 5. Abstract

Kahn E (1923). Studien über Vererbung und Entstehung geistiger Störungen. IV. Schizoid und Schizophrenie im Erbgang. Springer: Berlin.

Kallmann FJ (1938). The genetics of schizophrenia. Augustin: New York.

Schulz B (1940). Kinder schizophrener Elternpaare. Z Ges Neurol Psychiat 168:332-81.

Elsässer G (1952). Die Nachkommen geisteskranker Elternpaare. Thieme: Stuttgart.

Lewis AJ (1957). The offspring of parents both mentally ill. Acta Genet 7:349-65. Abstract

Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI Jr, Goldin LR, Bunney WE Jr. (1982). A family study of schizoaffective, bipolar I, bipolar II, unipolar and normal control probands. Arch Gen Psychiat 39:1157-67. Abstract

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Related News: With Two Affected Parents, Schizophrenia Risk in Offspring Skyrockets

Comment by:  Jehannine Austin
Submitted 19 March 2010
Posted 19 March 2010

The study recently published by Irving Gottesman and colleagues in the Archives has—as the authors point out—potentially important clinical implications. Using Denmark’s national registry data (>2.6 million individuals), the researchers calculated the cumulative incidences (to age 52) of psychiatric diagnoses in offspring of couples where one or both had previously been diagnosed with schizophrenia or bipolar disorder. The results clearly show that the probability of developing psychiatric illness is higher among offspring of individuals who have one parent with schizophrenia or bipolar disorder than among those who have no affected parents, and that the probability of developing psychiatric illness is highest among those who have both parents affected.

Probabilities that children will develop psychiatric disorders are of considerable interest amongst individuals with severe mental illnesses like schizophrenia and bipolar disorder. Further, American Psychiatric Association practice guidelines (American Psychiatric Association, 2002) for the treatment of individuals with bipolar disorder who are considering having children suggest that genetic counseling (which incorporates provision and discussion of risks for children to be affected) may be useful. Accordingly, Gottesman’s group points out that the probabilities documented in their paper may be useful for individuals with psychiatric disorders with regard to personal decision-making about issues such as childbearing. Indeed, we have previously shown that perceived risk for offspring to develop psychiatric illness may influence childbearing decisions (Austin et al., 2006).

It becomes relevant to question how the risks for offspring of individuals with psychiatric illness to develop severe mental illnesses are perceived by affected individuals. In an online survey, we asked 250 individuals with a history of psychotic illness or bipolar disorder what they thought was the chance for an individual with one affected parent to develop psychosis. We found that 43 percent of this group indicated that they thought the chance was 50 percent or greater (unpublished data).

Other commentary on this article highlighted that the probability of severe mental illness “skyrockets” when both parents are affected. But, for a sizable proportion of affected individuals who dramatically overestimate the chance for offspring to be affected, the figures derived by Gottesman’s group will actually be reassuring or lower than anticipated.

The figures reported by Gottesman’s group are a welcome resource for those of us who seek to provide individuals with severe mental illness with the most accurate probability estimates possible for these outcomes in the context of genetic counseling. As the authors point out, however, the probability figures they generated are “applicable to groups of people, not to the individuals themselves.” These figures are a useful foundation for the derivation of individualized probability estimates, in a manner that has been described elsewhere (Austin et al., 2008; Austin and Peay, 2006). No matter how reliable the study from which such probabilities are generated, however, they remain probabilities and, as John Adams writes, “Estimates of the probability of particular harms are quantified expressions of ignorance” (Adams, 2003). Essentially, we can’t say for sure whether a particular individual will develop severe mental illness or not.

References:

American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 Suppl):1-50. Abstract

Adams J. Risk and morality: three framing devices. In RV Ericson and A Doyle (Eds.), Risk and Morality. Toronto: University of Toronto Press, 2003:87-103.

Austin J, Smith GN, Honer WG. The genomic era and perceptions of psychotic disorders: Genetic risk estimation, associations with reproductive decisions and views about predictive testing. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(8):926-8. Abstract

Austin JC, Peay HL. Applications and limitations of empiric data in provision of recurrence risks for schizophrenia: A practical review for healthcare professionals providing clinical psychiatric genetics consultations. Clin Genet. 2006;70(3):177-87. Abstract

Austin JC, Palmer CG, Rosen-Sheidley B, Veach PM, Gettig E, Peay HL. Psychiatric disorders in clinical genetics II: Individualizing recurrence risks. J Genet Couns. 2008;17(1):18-29. Epub 2007 Dec 11. Abstract

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Related News: Schizophrenia Genetics 2: The Rise of GWAS

Comment by:  Chris Carter
Submitted 7 April 2010
Posted 8 April 2010

I wonder whether the relative lack of success in schizophrenia GWAS may be because the origin of schizophrenia may lie not so much in the genetic make-up of people with schizophrenia themselves, but in their prenatal experience, and possibly with the genes of the mother rather than with those of the offspring. Famine, rubella, influenza, herpes (HSV1 and HSV2), and poliovirus infection as well as high fever during pregnancy have all been listed as risk factors for the offspring developing schizophrenia in later life, as have maternal preeclampsia and obstetric complications. (See page at Polygenic Pathways for the many references.)

Maternal resistance to these effects is likely to be gene-dependent. Is it worth considering GWAS in the mothers rather than in the offspring?

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