21 December 2012. In the first genomewide association study (GWAS) of schizophrenia symptom dimensions, researchers report a polygenic effect on disorganized symptoms, which include formal thought disorder and bizarre behavior. First authors Ayman Fanous of the Veterans Affairs Medical Center in Washington, DC, and Baiyu Zhou of Albert Einstein College of Medicine in Bronx, New York, along with the Schizophrenia Psychiatric GWAS Consortium (PGC), published their findings online December 1 in the American Journal of Psychiatry.
An illness characterized almost as well by its heterogeneity as by its common features, schizophrenia comes with a wide range of symptoms and variation in illness course, symptom severity, and outcome. A number of studies have suggested that this heterogeneity is heritable (Cardno et al., 2001; Fanous and Kendler, 2008). In the current study, researchers probed the genetic basis for this clinical heterogeneity using both Molecular Genetics of Schizophrenia (MGS) and PGC study samples. This work was presented earlier this year at the World Congress of Psychiatric Genetics meeting (see SRF related conference story).
Fanous, Zhou, and colleagues first examined data from the MGS sample of 2,454 subjects with schizophrenia or schizoaffective disorder (Shi et al., 2009), all of whom had been assessed with the Lifetime Dimensions of Psychosis Scale. Though the scale consists of 14 items, including delusions, paranoia, hallucinations, blunted affect, and formal thought disorder, factor analysis of the scores on these items from the MGS sample identified three symptom categories—positive, negative/disorganized, and affective.
Even with this simplification, however, no single nucleotide polymorphism (SNP) of the 696,491 examined was significantly associated with any of these three symptom factors. This is not particularly surprising, given that larger sample sizes in the tens of thousands have been needed to detect schizophrenia-associated SNPs at a genomewide level of significance in past studies (see SRF related news story and SRF related conference story). Still, the authors highlighted 18 SNPs with promising p values less than 10-5 and found that these usually associated with a single symptom factor. Except for a signal in the major histocompatibility complex region of chromosome 6p21, these SNPs did not overlap with schizophrenia-associated SNPs detected in case-control designed GWAS, which suggests that genetic loci modulating symptoms may differ from those involved in schizophrenia vulnerability.
To see if these hints of association might signal something real, the researchers examined the symptom dimension-related SNPs in the PGC samples using a polygenic score analysis. A polygenic model, where thousands of alleles each contribute a small effect to schizophrenia on a population basis, was advanced by Gottesman and Shields (Gottesman and Shields, 1967) and has recently received experimental support (Purcell et al., 2009). The researchers sorted the symptom-related SNPs by varying levels of significance determined in the MGS sample, then evaluated the combined contributions of these SNPs in the PGC samples with a polygenic score. This revealed that the SNPs nominally associated with negative/disorganized symptoms were overrepresented in PGC cases compared to controls, though they explained only 0.05 percent of the variance in liability for schizophrenia. Subsequent analyses suggested that this effect was mainly due to disorganized symptoms of formal thought disorder and bizarre behavior rather than negative symptoms. Polygenic scores based on SNPs related to the positive or affective symptom dimensions did not differ between PGC cases and controls.
Standardizing clinical assessments of symptoms would greatly aid the identification of the relevant genetic factors, and a similar analysis of multiple PGC datasets is ongoing. The authors note that this “could shed additional light on whether significant associations can be observed between individual SNPs and symptom dimensions, and whether the polygenic effect on negative/disorganized symptoms can be replicated and strengthened despite the need to combine different types of rating systems from different studies.”—Allison A. Curley.
Fanous AH, Zhou B, Aggen SH, Bergen SE, Amdur RL, Duan J, Sanders AR, Shi J, Mowry BJ, Olincy A, Amin F, Cloninger CR, Silverman JM, Buccola NG, Byerley WF, Black DW, Freedman R, Dudbridge F, Holmans PA, Ripke S, Gejman PV, Kendler KS, Levinson DF. Genomewide association study of clinical dimensions of schizophrenia: polygenic effect on disorganized symptoms. Am J Psychiatry . 2012 Dec 1 ; 169(12):1309-17. Abstract