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Bridging the Gap Between Genes and Schizophrenia

26 August 2011. As the search for genetic variants related to schizophrenia and other psychiatric diseases continues, researchers have begun trying to piece together how exactly some of these variants contribute to disease. Two studies published in August in the Archives of General Psychiatry combine genotyping with brain imaging to discover associations between common variants and proposed intermediate or "endo-" phenotypes of brain structure and function. One study, led by Nicholas Schork at the University of California in San Diego, finds a single nucleotide polymorphism (SNP) on 15q12 that associates with cortical thickness and cognition in schizophrenia. The other study, led by Daniel Weinberger at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, links an SNP in ZNF804A to functional coupling between dorsal lateral prefrontal cortex and other regions of the brain.

These imaging genetics studies spur deeper thinking about just what associations between genetic variants and a disease mean. Researchers have begun to bridge this gap by focusing on more apparently tractable aspects of a disease, be it a discrete behavioral phenotype such as prepulse inhibition, or something closer to the underlying biology, such as changes in brain structure—both of which appear to be altered in schizophrenia. Relating genetic variants to these intermediate phenotypes may help discover more disease-related genes, or identify neural circuits that contribute to the disease (Meyer-Lindenberg et al., 2006). Though both new studies use brain imaging measures as an intermediate phenotype, one study takes the gene discovery approach, and the other a neural mechanism approach.

Thick or thin
First author Trygve Bakken and colleagues at UCSD and the University of Oslo, Norway, focused on cortical thickness as an intermediate phenotype of interest because it is highly heritable, and because thinner cortices are associated with schizophrenia and bipolar disorder, and with decreased cognitive performance in healthy individuals. To find genetic variants associated with cortical thickness, the researchers did a genomewide search of 597,198 SNPs to see whether any were associated with cortical thickness throughout the brain, as measured by magnetic resonance imaging (MRI) in 94 individuals with schizophrenia, 97 with bipolar disorder, and 181 controls.

Two closely linked SNPs turned up on 15q12, which lies within the region deleted in Prader-Willi and Angelman syndromes, and which contains imprinted genes thought to be important for brain development and function. CNVs nearby have also been implicated in autism (Hogart et al., 2010) and schizophrenia (Stefansson et al., 2008 and Ingason et al., 2011), though SNPs related to schizophrenia have not been found there. Consistent with this, the two SNPs found in this study did not confer risk for schizophrenia itself in their sample, but they were strongly associated with cortical thickness among individuals with schizophrenia, with genomewide significance (p = 1.1 x 10-8). This means that the group of individuals with schizophrenia homozygous for the major allele (GG) had, on average, thicker cortices than those homozygous for the minor allele (AA), with heterozygotes (AG) found in between. This effect amounted to a 3 percent reduction in cortical thickness per copy of the minor allele. The association was specific to schizophrenia, as it did not turn up for bipolar disorder, or for controls.

Because cortical thickness has been linked to cognition, the researchers examined whether the SNP could account for performance in three cognitive tests. As for cortical thickness, the SNP was found to be modestly associated with performance in individuals with schizophrenia, but not in those with bipolar disorder, or in controls. Though cognition is associated with multiple neural factors, the SNP seemed capable of explaining that portion of cognition related to cortical thickness.

Because the SNP doesn't associate with disease, the researchers suggest that this SNP-related cortical thinning has more to do with how the disease proceeds in the brain, rather than with any liability for schizophrenia itself. The researchers propose that the SNP may interact with various schizophrenia-related factors—genetic or environmental—to alter cortical thickness specifically in schizophrenia. The SNP lies within an intron of a putative gene LOC100128714, which is expressed in human brain. One idea is that this SNP could regulate nearby gene UBE3A, which controls excitatory synapse development; disruptions in this process could reduce dendritic arbors and neuropil volume, resulting in a thinner cortex. Future research will have to examine this region more thoroughly to find the causal variants and to understand the function of the protein encoded by LOC100128714.

Sibling connections
First author Roberta Rasetti and colleagues at NIMH took a different approach in the second study, starting with an SNP in ZNF804A already associated with schizophrenia (see SZGene entry), and then testing whether activity patterns in the brain were modulated by it. Specifically, they examined how neural activity was coordinated between the dorsal lateral prefrontal cortex (DLPFC) and other regions of the brain during a working memory task: the extent to which two areas of the brain co-vary their activity is a measure of their "functional connectivity." A previous study found that this same SNP (rs1344706) modulated functional connectivity between the DLPFC and other brain regions in healthy controls (Esslinger et al., 2009). To address whether this contributes in some way to schizophrenia, the researchers studied a group of 78 individuals with schizophrenia, 171 of their unaffected siblings, and 153 controls. Including unaffected siblings allowed the researchers to study brain activity in people who carry risk-associated genes without the confounding factors that come with actually being sick—something that helps distinguish heritable, susceptibility-related traits from states that reflect consequences of a disease.

Two methods of measuring functional connectivity gave largely similar results, finding abnormal coupling between the DLPFC and the hippocampus in the schizophrenia group and the sibling group, with the siblings showing connectivity values between those of the schizophrenia group and controls. A similar pattern was seen for DLPFC coupling with inferior parietal lobules (IPL) and with other regions of the PFC. Other aberrant DLPFC couplings turned up in schizophrenia—for example, with anterior cingulate cortex and with striatum—that were considered to be related to disease course ("state") because they were not found in siblings.

Genotype at the SNP was also associated with functional connectivity in controls, in the sibling group, and in schizophrenia. Individuals homozygous for the risk allele (AA) had disrupted DLPFC-hippocampal functional connectivity compared to those homozygous for the alternate C allele (CC), and heterozygotes (AC) had intermediate functional connectivity. This genetic association points to a role for ZNF804A in DLPFC-hippocampus coupling, and suggests that functional connectivity between these two regions constitutes a neural mechanism that is influenced by genetic risk for schizophrenia.

Future studies will have to replicate these findings in larger samples, as even genomewide genotyping outpaces brain scanning. Similarly, comprehensive behavioral testing is the rate-limiting factor in studies that try to associate genetic variants with neurophysiological or neurocognitive phenotypes related to schizophrenia. Undeterred, in April researchers reported that they had characterized 12 different behavioral endophenotypes—heritable measures that are impaired in schizophrenia, such as prepulse inhibition—in 534 study participants who had also been genotyped with an SNP array designed to probe 94 genes related to schizophrenia (Greenwood et al., 2011). They found 46 associated genes in all, with some associated with a single endophenotype and others with multiple endophenotypes. This suggests that there are different genetic routes to schizophrenia, and adds to the sense that delving into endo-/intermediate phenotypes will pave the way to a functional understanding of genetic variants related to schizophrenia.—Michele Solis.

Bakken TE, Bloss CS, Roddey JC, Joyner AH, Rimol LM, Djurovic S, Melle I, Sundet K, Agartz I, Andreassen OA, Dale AM, Schork NJ. Association of genetic variants on 15q12 with cortical thickness and cognition in schizophrenia. Arch Gen Psychiatry. 2011 Aug;68(8):781-90. Abstract

Rasetti R, Sambataro F, Chen Q, Callicott JH, Mattay VS, Weinberger DR. Altered Cortical Network Dynamics: A Potential Intermediate Phenotype for Schizophrenia and Association With ZNF804A. Arch Gen Psychiatry. 2011 Aug 1. Abstract

Comments on Related News

Related News: Interpret With Care: Cortical Thinning in Schizophrenia

Comment by:  Cynthia Shannon Weickert, SRF Advisor
Submitted 4 January 2012
Posted 4 January 2012

Plump Enough
Thanks for your thought-provoking review of structural MRI changes in schizophrenia. I had a couple of quick comments.

You make the statement that, "Though cortical thickness itself is below the resolution of typical MRI, image analysis algorithms can now infer thickness across the entire cortical sheet as it winds its way throughout the brain." I thought sMRI gathers information for about 2 mm cubed or so. So maybe the point to make is that cortex thickness is not below the resolution, but the putative change in thickness is below the resolution. It would be interesting to know if the putative change in cortical thickness in schizophrenia could be better viewed with 3T or 7T scanners.

Also, I wonder how to interpret decreases in volume over five years that seem to be as much as 5 percent in some areas. How long could this continue to be progressive at this rate, and what would be the final cortical volume expected in the final decade of life? For example, if the DLPFC BA46 is about 3,500 microns thick, then a 5 percent loss/five years over 20 years would leave you with about 2,850 microns, and that would be about a 20 percent decrease in thickness. While postmortem studies may be limited, as Karoly points out, certainly we know that the frontal cortex is still "plump enough" to define cyto-architecturally, and to examine at the histological level. We also consider that there is about a 10 percent loss in cortical thickness in people with schizophrenia. Certainly, the cortex does not degenerate completely as would be expected with relentless progression of loss and accumulated deterioration of cortical grey matter over time.

Thus, this is an interesting issue, but many questions remain. Is there a lot of case-to-case variability that underlies these averages such that some cases lose more cortical volume and some do not lose any at all? Could it be that, while there is cortical volume loss, there are some patients in whom this loss slows or even reverses naturally over the course of the disease? What is the physical substrate of such cortical volume loss in people with schizophrenia? Can we prevent cortical volume loss over time, and would this be beneficial to patient outcomes?

View all comments by Cynthia Shannon Weickert