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More Evidence Confirms Relevance of Risk Allele to Schizophrenia

September 5, 2012

The rs1344706 SNP on the ZNF804a gene was found to correlate with the volume of cortical white matter in schizophrenia patients and healthy control subjects, according to a report published Sept. 3 in Archives of General Psychiatry.

This SNP also correlated with severity of hallucinations and delusions in the patients with schizophrenia.

“Thus, our study further strengthens the case for rs1344706 being of relevance to schizophrenia,” said Dr. Thomas H. Wassink of the University of Iowa, Iowa City, and his associates.

Numerous studies have tied the rs1344706 SNP to several phenotypic traits of schizophrenia, including brain activation patterns, symptomatology, cognitive abilities, and brain structure. To examine in greater detail the relationship between this genetic variant and the volume of various brain structures, Dr. Wassink and his colleagues examined high-resolution brain MRIs from 335 patients with schizophrenia spectrum disorders and 198 healthy volunteers who had no medical, neurologic, or psychiatric illnesses and no first-degree relatives with schizophrenia.

Using the Comprehensive Assessment of Symptoms and History, the patients were diagnosed as having schizophrenia (310 subjects), schizoaffective disorder (21 subjects), delusional disorder (2 subjects), schizophreniform disorder (1 subject), or schizotypal personality disorder (1 subject).

The mean age of both the patients and the controls was approximately 31 years, and more than 90% of both groups were of white ethnicity.

In schizophrenia patients, the rs1344706 SNP was significantly associated with greater white matter volume in both the cortex and the frontal lobe. The highest-risk allele, carried by 126 patients, correlated with the greatest “excess” volume. The intermediate-risk allele, carried by 165 patients, correlated with intermediate “excess” volume. And the lowest-risk allele, carried by 44 patients, correlated with the lowest “excess” volume

However, the rs1344706 SNP was not significantly associated with greater grey matter volume in the schizophrenia group. This finding is contrary to that of 2 previous studies, the investigators noted (Arch. Gen. Psych. 2012;69:885-92).

The results were similar for the control subjects. In this group, 69 carried the highest-risk allele, 105 the intermediate-risk allele, and 24 the lowest-risk allele.

The rs1344706 SNP also exerted a significant effect on psychotic dimension scores, with the highest-risk allele correlating with the most severe hallucinations and delusions. In contrast, negative symptom and disorganized symptom dimensions were not related to rs1344706 status.

“This concordance of associations is supported by previous studies relating symptoms to [white matter] structure and function. Individuals at high risk for developing psychotic disorders who undergo MRI and who then go on to develop psychosis, for example, have increased [white matter] volume compared with high-risk individuals who do not go on to develop psychosis,” Dr. Wassink and his colleagues said.

Although the study findings largely confirm those of previous studies, the magnitude of the genetic variant’s effect on brain volume was much smaller in this study than in previous studies. The rs1344706 SNP accounted for only 1.1% of the difference in total cortical white matter volume among control subjects and only 2.0% of the difference among schizophrenia subjects in this study, in contrast to the 15% estimate in previous studies. “Our estimate may be more reliable given our larger sample size and the low likelihood that a single polymorphism would have such a strong effect on the genetically complex trait of brain structure volume,” the researchers said.

The results of this study add to the growing body of evidence suggesting that the risk allele of rs1347706 “is associated with a distinctive set of phenotypic features” in both schizophrenia patients and health controls, they added.

This study was supported in part by the National Institute of Mental Health. No financial conflicts of interest were reported.



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