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We're very thankful to Kate Burdick of Albert Einstein College of Medicine in New York City for sharing the following report on some of the presentations at the World Congress on Psychiatric Genetics (WCPG), held October 28 to November 1 in Cagliari, Italy.
20 December 2006. In the late 1960s, Gottesman and Shields used the term “endophenotype” to describe traits that may serve as biomarkers mediating between genotype and an observable phenotype. The endophenotype concept was originally proposed as a method by which researchers could reduce the heterogeneity and complexity of a measured phenotype (i.e., psychiatric diagnosis) by utilizing traits that correlate with affected status but are simpler in their behavioral and genetic architecture (i.e., working memory). Inasmuch as these traits might be more closely associated with gene action, endophenotypes would provide a stronger link to specific genetic loci, making the mapping of candidate genes for the complex phenotype more successful (see SRF Live Discussion led by Irving Gottesman). While this specific use of endophenotypes in psychiatric genetics has arguably never been wholly successful, the measurement of disease-associated traits and the investigation of the underlying genetic contributors to these traits continue to be a critical focus of genetic studies. The practical use of endophenotypes as a means to elucidate the neurobiological functions of candidate genes that have already been linked to susceptibility to psychiatric diagnosis was the topic of several presentations at the recent WCPG.
In an oral session specifically dedicated to endophenotypes, my colleague Anil Malhotra, from Zucker Hillside Hospital in New York City, presented data on structural neuroimaging parameters and symptom severity measures related to variation in the DISC1 gene. He reported that the minor allele (phe) of the DISC1 functional variant in exon 9 (leu607phe), previously shown to increase risk for schizophrenia, was associated with reduced grey matter in the superior frontal gyrus and the anterior cingulate in both patients with schizophrenia and healthy controls. Further, schizophrenia patients who carried the phe allele had significantly greater severity of hallucinations than leu/leu homozygotes. These data provide some insight into the potential mechanisms through which this SNP might influence risk for schizophrenia.
In the same session, Gary Donohoe from Aiden Corvin’s group at the University of Dublin, Ireland, presented on clinical, cognitive, and neurophysiological phenotypes associated to the dysbindin gene (DTNBP1). In previous work, this group identified a haplotype in the DTNBP1 gene that increased risk for schizophrenia, and they have subsequently tested for its effects on multiple endophenotypes. Donohoe presented data suggesting that carriers of the risk haplotype were significantly more impaired on both P1 response and spatial working memory measures, implicating a role for DTNBP1 in both early and later information processing. Additionally, he provided evidence that the risk haplotype was associated with reduced affective symptoms in patients with schizophrenia, suggesting that while DTNBP1 increases susceptibility to schizophrenia, the same variant may in fact be protective against affective symptomatology in schizophrenia. This protection against affective symptoms may be specific to patients with schizophrenia, as these data are somewhat inconsistent with a poster also presented at WCPG by Chi-Un Pae of the Catholic University of Korea in Seoul, which reported a significant association of a haplotype in DTNBP1 with affective disorders (both bipolar and unipolar diagnoses).
Juho Olavi Peltonen from Leena Peltonen’s group at the University of Helsinki, Finland, presented novel evidence that the reelin gene (RELN) also impacts cognition in patients with schizophrenia. Based on initial positional evidence of linkage to 7q22 and data suggesting that the RELN gene is associated with key aspects of neuronal development, this group tested for RELN’s effects on cognitive processing in 186 schizophrenia families, using five microsatellite markers. They found that the marker most highly associated with schizophrenia was also strongly associated with impaired performance on both verbal and visual working memory measures, implicating a potential role for RELN in frontal brain functions.
A second strategy that uses endophenotypes to enhance power in genetic studies is to employ endophenotypic traits to subtype a sample, or to refine the diagnostic categorization of patients by utilizing dimensional aspects of the illness being studied (e.g., delusions, hallucinations, or cognitive impairment). In a session on bipolar disorder at WCPG, a number of presentations were focused on this approach. Fernando Goes, working with James Potash at Johns Hopkins University in Baltimore, Maryland, presented evidence for the utility in subtyping bipolar patients on the basis of mood-incongruent psychotic features. In 708 families derived from the NIMH Genetics Initiative Bipolar Collaborative sample, familial aggregation was evident for mood-incongruent psychotic features but not for mood-congruent psychosis. The use of the bipolar patients positive for mood incongruence increased evidence for linkage on 13q21-33 (LOD = 2.99) and 2p11-q14 (LOD = 3.15), regions previously associated with schizophrenia.
In the same session, Marian Hamshere from the Cardiff University group in the United Kingdom presented similar evidence of mood incongruence as a useful subtyping trait in patients with bipolar disorder. She presented data from a genome-wide linkage study of 381 affected relative pairs, conditioned by presence of mood incongruence. Significant familiality of mood incongruence was reported in addition to evidence for linkage in three chromosomal regions: 1q32.3 (LOD = 4.15), 7p13 (LOD = 3.32), and 20q13.31 (LOD = 2.98). These data, albeit in different regions, are consistent with the NIMH data above and with the notion that power can be significantly enhanced using endophenotypic traits to subtype the population of interest in psychiatric genetics.
There were a number of other oral presentations and posters that were focused on the use of endophenotypes as a method to enhance power and elucidate potential underlying biological functions of candidate genes. This summary is in no way comprehensive but is intended to highlight the continued importance of carefully assessing clinical traits, such as cognitive performance, neuroimaging parameters, and symptom severity measures, which may prove advantageous as the search for genetic markers in complex psychiatric diseases moves forward.—Katherine Burdick.
Editor’s note: We would welcome updates, from the authors or other attendees, on any other meeting presentations in this vein. Just leave a comment below!