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Dissecting Phenotype to Approach Genetics of Schizophrenia

4 April 2013. A close look at the genetic basis of 12 measures of brain function that are altered or impaired in people with schizophrenia turns up one clear clue and several possible leads. Published online March 20 in the American Journal of Psychiatry, the study measured brain functions ranging from memory to eye movement in over 1,000 people with schizophrenia and their relatives. Conducted by the Consortium on the Genetics of Schizophrenia (COGS) and led by David Braff at the University of California in San Diego, the study reports one association with genomewide significance: chromosome 3p14 was associated with the antisaccade task, a measure of the ability to inhibit a movement. Another 11 regions had “suggestive” evidence of association with other measures, including prepulse inhibition, sensorimotor dexterity, and verbal learning.

Because schizophrenia itself is a mix of symptoms that varies from person to person, different genes or groups of genes may be disrupted in different people. To cut through this complexity, researchers have advocated tracking down the genetic basis of certain features of brain functions that are inherited, and related to schizophrenia, called “endophenotypes” (Gottesman and Gould, 2003; see SRF related news story). For example, the antisaccade task requires people to suppress the natural tendency to orient their eyes to a peripheral target. This ability is impaired in people with schizophrenia and their unaffected relatives, compared to the general population, which suggests that the task gives a readout of an aspect of brain function that marks risk for the disorder. The new study presents the most comprehensive look at endophenotypes for schizophrenia and their genetic underpinnings.

The working assumption is that finding the genes contributing to these endophenotypes might finger genes involved in schizophrenia, because it is easier to find the genetic roots of a consistent phenotype such as eye tracking than a variable one like schizophrenia (Lien et al., 2010). The research is also based on the notion that endophenotypes may lie closer to the causal perturbations of genes than the symptoms of schizophrenia. What’s more, because something is known about the brain processes involved in an endophenotype, a biological understanding of any fingered genes might be easier to come by (Almasy et al., 2008).

The COGS turn
But it’s a huge undertaking to measure endophenotypes in a sample large enough to give meaningful genetic results. Drawing from seven different sites, the COGS team assayed 1,286 people from 296 families on 12 different measures of brain function. In 2007, the COGS team reported on the heritability of these 12 measures (see SRF related news story), and in 2011, they did a first pass look of the genetics underlying endophenotypes with a candidate gene study (see SRF related news story). The new study uses a linkage scan of the entire genome to identify chromosomal regions likely harboring genes involved in these endophenotypes (see SRF schizophrenia genetics primer). Although linkage studies do not have the high-definition resolution found in current genomewide association studies (GWAS), they can detect summed contributions of different genetic variants that may be operating in different families.

First author Tiffany Greenwood and colleagues genotyped the study participants on about 6,000 different single nucleotide polymorphisms (SNPs). Each family consisted of at least one person with schizophrenia, an unaffected sibling, and both parents. By comparing their genotypes to their performance on each individual endophenotype task, the researchers found many associated linkage peaks—glimmers of a genetic signal along the chromosomes. But only the peak at chromosome 3p14 associated with the antisaccade task met statistical significance, with a log of odds (LOD) score of 4. Underneath this peak live several brain-expressed genes, including ataxin 7 (ATXN7), a gene disrupted in a neurodegenerative disorder.

Suggestion box
The researchers noted 11 other suggestive regions with LOD scores over 2. These included chromosomal regions 2p25 and 16q23 for spatial processing, 2q24 and 2q32 for sensorimotor dexterity, 5p15 for prepulse inhibition, and 8q24 for verbal learning. Which genes might be driving these signals is unclear, though some already known to schizophrenia researchers lie underneath the peaks, like ZNF804A in one of the peaks for sensorimotor dexterity, or a dopamine transporter gene (SCC6A3/DAT) in the peak for prepulse inhibition. None of the associations in the study were corrected for multiple comparisons.

The study did not have enough people with schizophrenia to weigh in on whether these endophenotypes actually provided stronger genetic signals than those that would have turned up by simply categorizing the participants as affected or unaffected. Stronger signals may come with larger sample sizes, or refined endophenotypes. In the meantime, researchers will have to steel themselves for the possibility that the genetic architectures for endophenotypes are just as complicated as the one for schizophrenia.—Michele Solis.

Reference:
Greenwood TA, Swerdlow NR, Gur RE, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RC, Lazzeroni LC, Nuechterlein KH, Olincy A, Radant AD, Ray A, Schork NJ, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Sugar CA, Tsuang DW, Tsuang MT, Turetsky BI, Light GA, Braff DL. Genome-Wide Linkage Analyses of 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia. Am J Psychiatry. 2013 Mar 20. Abstract

 
Comments on News and Primary Papers
Primary Papers: Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia.

Comment by:  Irving Gottesman
Submitted 27 March 2013 Posted 1 April 2013
  I recommend this paper

This is a landmark paper, one that complements the recent Lancet paper on the GWAS for five major psychiatric disorders (see SRF related news story). It would be of interest to extend the analyses, using the techniques of Glahn et al. (Glahn et al., 2012) for major affective disorders, that rank-orders the endophenotypes ("ERV") for their overall importance across numerous domains of data sources, including, in their case, imaging data.

References:

Glahn DC, Curran JE, Winkler AM, Carless MA, Kent JW, Charlesworth JC, Johnson MP, Göring HH, Cole SA, Dyer TD, Moses EK, Olvera RL, Kochunov P, Duggirala R, Fox PT, Almasy L, Blangero J. High dimensional endophenotype ranking in the search for major depression risk genes. Biol Psychiatry . 2012 Jan 1 ; 71(1):6-14. Abstract

View all comments by Irving Gottesman


Primary Papers: Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia.

Comment by:  Timothea Toulopoulou
Submitted 17 April 2013 Posted 17 April 2013

Some of the very best schizophrenia scientists in the world are part of this consortium, and they are to be congratulated for making this work possible. I’d be interested to see if we can replicate these findings in our Wellcome Trust Case Control Consortium 2 (WTCCC2) collaboration, which uses similar endophenotypes. One comment: given the correlation between the endophenotypes, I would have been tempted to do proper multivariate analyses (SEM) to get the latent factor that captures the variance common to all endophenotypes before proceeding with linkage analyses. In this way, the variance specific to each endophenotype would be separate from the robust and reliable variance common to all endophenotypes.

View all comments by Timothea Toulopoulou

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