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Nine Dimensions of Schizophrenia Found to Run in Families

24 June 2009. You might call it the “divide and conquer strategy” for finding the genes responsible for schizophrenia; it involves divvying up the manifestations of the illness into related groupings and then seeking the genes that contribute to each grouping. In a paper in the June Archives of General Psychiatry, Ann E. Pulver and others at Johns Hopkins University in Baltimore, Maryland, take steps in that direction. They sought to identify the dimensions that tie together various signs and symptoms of schizophrenia, including indicators of social functioning, occupational performance, and prodromal features. All nine of the dimensions that they found, including some novel ones, tended to cluster in families.

Some researchers argue that the complexity of schizophrenia is hampering the search for its causes, and that breaking the disorder down into more homogeneous parts, at the level of phenotypes or the even more basic level of endophenotypes, may speed progress (see SRF live discussion; see SRF live discussion; see SRF related news story). There has been some research on discerning the factor structure of schizophrenia, with inconsistent results (for a review, see Peralta and Cuesta, 2001; for more recent studies, see Villalta-Gil et al., 2006; Emsley et al., 2003). In tune with that thinking, those involved in the new study, including first author John A. McGrath, used factor analysis to unearth leads for genetic studies.

According to McGrath and colleagues, schizophrenia “is likely several related disorders with varying and sometimes overlapping genetic underpinnings, some of which affect clinical and course features.” This view led them to examine an unusually broad set of schizophrenia manifestations. Specifically, they tested a set of 73 items, which went beyond positive symptoms, negative symptoms, affect, and disorganized thoughts and behavior. They also included measures of disturbed social functioning during childhood and adolescence, social and occupational decline, and academic performance.

The data came from 1,199 people who met criteria for schizophrenia or schizoaffective disorder. Most were living in the United States, although a few subjects from Canada, Greece, Italy, Poland, and Israel also participated. The sample included 513 outbred subjects and 686 Jews of European ancestry. Most of the outbred subjects were of white European descent; 6 percent were African American. Nearly all of the Jews were of Ashkenazi background.

Information on each subject’s signs, symptoms, and psychiatric history came from clinical interviews, medical records, and proxy reports. At least two diagnosticians reviewed the data to render consensus judgments regarding diagnoses and other key information.

Something old, something new
The researchers found nine dimensions that explain 35 percent of the variance in their data, a smaller percentage of the variance than found in other studies (e.g., Villalta-Gil et al., 2006; Emsley et al., 2001). McGrath and colleagues attribute this, in part, to the way they imputed missing data.

Five of the factors echo those in many other factor analytic studies of schizophrenia, including those tapping hallucinations, negative symptoms, affective symptoms, disorganization, and Schneiderian first-rank symptoms. The last reflects signs and symptoms that psychiatrist Kurt Schneider (Schneider, 1974) considered central to schizophrenia, such as hearing one’s thoughts broadcast to other people, attributing one’s thoughts to insertion by others, and other forms of delusions.

In addition, McGrath and colleagues report four dimensions that they describe as new to factor analytic studies in schizophrenia, although they mirror known features of schizophrenia. For instance, the highest-loading items on the disability/impairment factor pertain to work functioning. That factor correlated only weakly with their scholastic factor, which includes aspects of elementary, high school, and college performance. The prodromal factor encompasses warning signs, such as role impairment, avoidance of social interactions, odd behavior, and bizarre thoughts, which may precede full-blown schizophrenia.

A final factor consisted mainly of items related to childhood and adolescent sociability. This complements past findings of an adult disordered social relations factor (e.g., Emsley et al., 2001; Toomey et al., 1997).

In this study, depression and mania formed one factor rather than separating into two, perhaps due to its inclusion of relatively few mood items, McGrath and colleagues speculate. Furthermore, their affective factor correlated only weakly and inversely with the negative symptoms dimension, which, they write, suggests that they arise independently.

Factoring in family ties
Of course, whether these dimensions will speed the hunt for elusive schizophrenia genes depends, in part, on their heritability. While McGrath and associates did not design their study to test heritability per se, they were able to probe whether the factors they found clustered in families. They used a heritability measure, the ratio of polygenic variance to total variance, to gauge familiality, although they caution against using it to infer heritability in the general population.

To map out family ties of the 1,199 subjects, the study used information on 553 of their family members. Most families (714) had only one member with schizophrenia, but 207 had more than one. The results hint that all of the nine factors run in families. In particular, disability/impairment showed the highest heritability at 0.61, with disorganization coming in at a nearly identical at 0.60. Child and adolescent sociability showed the lowest at 0.27. Heritability for the other factors ranged from 0.36 to 0.53.

These findings contrast with those from a recent review and meta-analysis (Rietkerk et al., 2008). It evaluated the evidence for genetic contributions to three dimensions—namely, reality distortion, as evidenced by hallucinations and delusions; psychomotor poverty, manifested by flat affect, scant speech, and decreased spontaneous movement; and disorganization, which includes formal thought disorder, inappropriate affect, and strange behavior. Only disorganization, one of the most familial factors in the McGrath study, showed clear evidence of genetic influence.

Having generated factors that they hoped would provide leads for genetic studies, the researchers are putting them to the test. They are now using the factor scores as phenotypes in quantitative trait locus linkage and association studies.—Victoria L. Wilcox.

Reference:
McGrath JA, Avramopoulous D, Lasseter VK, Wolyniec PS, Fallin MD, Liang K-Y, Nestadt G, Thornquist MH, Luke JR, Chen P-L, Valle D, Pulver AE. Familiality of novel factorial dimensions of schizophrenia. Arch Gen Psychiatry. 2009 June; 66(6):591-600. Abstract

Comments on News and Primary Papers
Comment by:  John McGrath, SRF Advisor
Submitted 24 June 2009
Posted 24 June 2009

John A. McGrath and I (John J. McGrath—no relation) welcome any other like-named or like-minded researchers to contribute further to the quest to resolve the heterogeneity of the poorly understood group of brain disorders currently lumped under the label “schizophrenia.” This interim label has tenaciously guided our research efforts for decades, despite the fact that the research community is well aware of its deficiencies. Like intellectual fly-paper, the problems with this diagnostic label have probably shortened the life of many able researchers. Can we ever hope to fractionate the underlying disorders into more meaningful groupings?

John A. McGrath and colleagues from Baltimore have looked for heritability of a broad range of symptoms and measures of disability. All factors were found to be heritable, but some were more heritable than others. This is an interesting outcome. The challenge for the research community will be what to do next.

I would like to add a few friendly comments in order to stimulate debate. These comments reflect my personal biases. I am happy to acknowledge uncertainty around these comments and happy to revise my opinions in the face of data (hint—add your dissenting comments below so we can get some debate going).

1. Do we expect that the genetic architecture of schizophrenia will map obediently onto surface level phenotypes? With our current limited knowledge of developmental neurobiology and systems neuroscience, how optimistic should we be about linking factor-derived surface-level phenotypes with upstream gene variation? Would researchers interested in the genetic architecture underlying asthma gain much additional traction if they divided up cases into high-pitched versus low-pitched wheezing, polyphonic versus monotonic wheezing, wheezing with frequent versus infrequent coughing, etc. I am not arguing that this is not worth doing—it may provide important clues. We keep looking for the “low hanging fruit”—but is this realistic?

2. Can we enrich the phenotypes? Would the factors be more informative if they also included laboratory-based variables (e.g., brain structure, electrophysiology, eye movement, niacin flush, etc.) (Hallmayer et al., 2003; Price et al., 2006)? Would the “gain be worth the pain”? What do experts think?

3. How do we interpret the “scholastic” factor? This factor is particularly interesting in light of the convergent evidence from schizophrenia epidemiology. A range of population-based cohort studies have shown that individuals who go on to develop schizophrenia are more likely to have premorbid neurocognitive impairment (Maccabe, 2008; Welham et al., 2009). However, this intermediate phenotype is associated with a very wide range of adverse clinical and educational outcomes. On the one hand, this non-specificity is a cause for celebration—if we can find public health measures that can rescue these vulnerable brains, we may be able to avert much more disability than that only related to schizophrenia (Rose, 1992). On the other hand, it is a gloomy prospect if we acknowledge that there are an infinite number of ways to disrupt optimal brain development, and that reduced cognitive reserve is probably an intermediate phenotype of a wide range of clinical conditions (leaving aside educational and economic outcomes).

4. Where to now? Pulver and colleagues have already linked one of the factors with a candidate gene (Chen et al., 2009). Should we invest time in reclassifying existing or new patient groups based on surface level phenotypes and keep looking for new clues? This will be important, but I argue we know too little about normal brain function to be able to build realistic models linking genetic factors and surface level phenotypes. We should keep trying to build models based on the imperfect existing knowledge, but mostly these will be wrong. The best investment for our field would be to use the clues from genetics and risk factor epidemiology to help drive more neuroscience discovery (McGrath and Richards, 2009). The more knowledge we have about the brain, the less ridiculous our models will be. The faint clues that may emerge from genetic studies using taxons based on surface level phenotypes could be important catalysts for discovery in basic neuroscience. We have decades of work ahead of us, but the science is tractable.

References:

Chen, P. L., D. Avramopoulos, et al. (2009). Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. Am J Hum Genet 84(1): 21-34. Abstract

Hallmayer, J. F., A. Jablensky, et al. (2003). Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia. Mol Psychiatry 8(5): 511-23. Abstract

Maccabe, J. H. (2008). Population-based cohort studies on premorbid cognitive function in schizophrenia. Epidemiol Rev 30: 77-83. Abstract

McGrath, J. A., D. Avramopoulos, et al. (2009). Familiality of novel factorial dimensions of schizophrenia. Arch Gen Psychiatry 66(6): 591-600. Abstract

McGrath, J. J. and L. J. Richards. (2009). Why schizophrenia epidemiology needs neurobiology--and vice versa. Schizophr Bull 35(3): 577-81. Abstract

Price, G. W., P. T. Michie, et al. (2006). A multivariate electrophysiological endophenotype, from a unitary cohort, shows greater research utility than any single feature in the Western Australian family study of schizophrenia. Biol Psychiatry 60(1): 1-10. Abstract

Rose, G. (1992). The Strategy of Preventive Medicine. Oxford, Oxford University Press.

Welham, J., M. Isohanni, et al. (2009). The antecedents of schizophrenia: a review of birth cohort studies. Schizophr Bull 35(3): 603-23. Abstract

View all comments by John McGrathComment by:  Timothea Toulopoulou
Submitted 15 July 2009
Posted 15 July 2009

While a number of genetic loci that appear to represent an increased susceptibility to schizophrenia have been identified, linkage, candidate gene and whole genome scan approaches have been largely unsuccessful in identifying these genes in any consistent way. This is partly because the clinical characteristics of schizophrenia are very far along the pathophysiological chain that extends from genes, through proteins, neurons, cognition, behavior, and symptoms, and finally to the DSM-IV construct of schizophrenia. Phenotypes closer to the gene effects in the pathophysiological pathway are better placed to help to untangle the genetic components of the illness.

McGrath and colleagues analyses of 73 indicators resulting in nine sign and symptom factors, or dimensions, could provide alternative phenotypes for molecular genetic studies in place of the DSM-IV construct of schizophrenia, assuming, of course, that twin and adoption studies show that they are heritable. McGrath and colleagues used a large number of core symptoms of schizophrenia and additional indicators of social, work, and educational dysfunction. It is the first study to demonstrate familial aggregation of child/adolescent sociability, scholastic performance, disability/impairment, and prodromal factors. These factors could be used to refine the schizophrenia phenotype; stratifying patients by their factor scores might help to identify the risk alleles that increase liability to this disorder.

View all comments by Timothea Toulopoulou

Comments on Related News


Related News: ICOSR 2007—DSM-V Stirs Debate and Discussion

Comment by:  Jane Nangle
Submitted 3 April 2007
Posted 5 April 2007

I feel it is better to characterise the symptoms of schizophrenia as falling into two categories: "active" and "passive." None of the symptoms is "positive" in a layperson's understanding of the word, and all of them are "negative." If the APA is to change the DSM language regarding schizophrenia, they should also correct the unfortunate positive/negative terminology.

View all comments by Jane Nangle

Related News: ICOSR 2007—DSM-V Stirs Debate and Discussion

Comment by:  Christopher Holly
Submitted 6 April 2007
Posted 10 April 2007

Many patients seen in the emergency room at the hospital where I work are still calling Bipolar Spectrum Disorder by its original diagnostic designation, "manic depression." Honestly, we as a mental health care community must ask, what is in a name? Schizophrenia is well know as a term; perhaps instead of changing the name of the classification, we should spend time educating people what it means and how to live well with it.

View all comments by Christopher Holly

Related News: ICOSR 2007—DSM-V Stirs Debate and Discussion

Comment by:  Patricia Estani
Submitted 30 April 2007
Posted 1 May 2007

I would like to agree with the general concept that the categorical classifications should disappear, at least the current phenomenological classifications (DSM-IV). These kinds of classifications are a large listing of phenomenological symptoms that do not meet any neurobiological criteria according to the last scientific research data in the field of psychiatry, especially within the field of psychiatric genetics data.

The dimensional classifications are more adapted to the newest research in the neurobiology of schizophrenia, possibly a gradual combination of less categorical and more dimensional classifications, as Dr. William Carpenter explained at the ICOSR.

Summing up, I think that the central issues of the discussion are represented by the following points:

1. The inclusion of the concept of endophenotypes (see SRF Live Discussion, led by I. Gottesman) and their biomarkers in the new classifications.

2. The inclusion of dimensional classifications.

Certainly, the inclusion of endophenotypes, explained by Dr. Guvant Thakar, is the only real innovation. I think that the combination of all of these points will make new classifications more useful tools for both clinicians and scientific researchers.

View all comments by Patricia Estani

Related News: ICOSR 2007—DSM-V Stirs Debate and Discussion

Comment by:  David Yates
Submitted 7 May 2007
Posted 7 May 2007

My family is unlucky in that two members have had affective illnesses and one has schizophrenia, although there is no family history on either side. I have no difficulty in the diagnoses and no difficulty in seeing them as different entities. Perhaps the point is that observation over a degree of duration brings clarity when initial presentation or point examination does not always do that.

In the United Kingdom one other argument for keeping the diagnosis schizophrenia remains for those who are family carers—despite the present 'walk on the other side and keep your eyes down attitude,' the amount of funding that goes to the care and treatment of the those with the illness can be scrutinised, and any discrepant lack of it—when say, compared with the funding share going to less serious conditions—can be pointed out. You will get what you pay for.

View all comments by David Yates