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ICOSR 2017: Endophenotypes in Schizophrenia Research: A Tribute to Irv Gottesman

25 Apr 2017

As part of our ongoing coverage of the 2017 International Congress on Schizophrenia Research (ICOSR), held March 25-28 in San Diego, we bring you session summaries from some of the participants in the Young Investigator program. We are, as always, grateful for the gracious assistance of YI program directors Laura Rowland and Scott Sponheim, as well as Michelle Tidwell of the ICOSR staff. For this report, we thank Bengi Baran, PhD, of Massachusetts General Hospital and Harvard Medical School.

One of the well-attended symposia at the ICOSR 2017 meeting in San Diego, California, was titled “Endophenotypes: The Legacy and Future of Irv Gottesman’s Work.” Irving Gottesman was a pioneer in psychiatric genetics who introduced the concepts of epigenetics and endophenotypes to schizophrenia research. His groundbreaking research helped transform the field from archaic concepts such as “refrigerator mothers” to the recognition that schizophrenia is a heritable polygenic disorder. He proposed that we will only be able to understand the complex genetic nature of schizophrenia with the identification of endophenotypes, “internal phenotypes” discoverable by a “biochemical test or microscopic examination” (Gottesman and Shields, 1972; Gottesman and Gould, 2003). The primary goals of this session were to recognize Gottesman’s contributions to the field and to the researchers (see SRF obituary and testimonials), and discuss the current state and future of the search for schizophrenia endophenotypes.

David Braff of the University of California, San Diego, explained that the goal of endophenotype research is to “unlock the secrets of schizophrenia and fill in the gene-to-phene gap in our knowledge.” Two influential consortia led by Braff―the COGS-1 family study and COGS-2 case-control study―identified 12 cognitive and neurophysiological endophenotypes, and quantified relationships between these endophenotypes and schizophrenia risk genes (see, e.g., SRF news here and here). The most innovative aspect of COGS-1 was the recruitment of schizophrenia probands along with both parents and an unaffected sibling, which allowed for identification of de novo mutations. These efforts led to the identification of a 42-gene pathway implicating glutamatergic dysfunction in the etiology of schizophrenia. COGS and other consortia such as Project Among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), the Multiplex Multigenerational Investigation of Schizophrenia (MGI), Psychosis Endophenotypes International Consortium (PEIC), and Bipolar and Schizophrenia Network for Intermediate Phenotypes (B-SNIP) are actively investigating how endophenotype deficits relate to genetic variations and to real-world functioning.

Next, David Glahn of Yale University emphasized the importance of quantification of endophenotypes. While several putative schizophrenia endophenotypes have been put forward, he cautioned that the field has been neither restrictive nor consistent in the use of the term. Glahn introduced the Endophenotyping Ranking Value (ERV; wittily named after Irv Gottesman). ERV is a measure of co-variance calculated as the square root of the heritability of the disease and the square root of the heritability of the endophenotype, multiplied by their genetic correlation. This ranges between 0 and 1 and indicates to what extent the endophenotype and the disease are influenced by shared genetic factors.

Brett Clementz of the University of Georgia delivered the next presentation in place of Carol Tamminga, who was not able to join the session due to a scheduling conflict. Clementz focused on eye movement dysfunction in schizophrenia and asked a critical question: Can simple measures help us solve the complex puzzle of schizophrenia? Specifically, his work in progress reveals that structural variation in cortical thickness in medial and lateral prefrontal and parietal regions is related to smooth-pursuit eye movement dysfunction in both probands and their relatives.

He was followed by Raquel Gur of the University of Pennsylvania, who focused on quantification of cognitive impairments in schizophrenia. Gur introduced the Computerized Neurocognitive Battery (NCB), which is designed specifically to meet the needs of large-scale genetics studies. Gur explained that NCB is a reliable, valid, and efficient tool, and is pertinent for early identification and intervention efforts. Performance profiles on the NCB are consistent across different schizophrenia consortia, and schizophrenia polygenic risk scores are significantly correlated with cognitive deficits as early as nine years of age. Along with functional imaging evidence, deficits on the NCB are suggestive of frontotemporal abnormalities. Importantly, Gur explained that there has been a paradigm shift in schizophrenia research, namely that recent efforts are focused not on mere symptom classification but on identification of biomarkers. Gur went on to propose that this paradigm shift should allow researchers to bridge the pediatrics and adult divide by characterization of the developmental trajectories of biomarkers.

Finally, Keith Nuechterlein of the University of California, Los Angeles, the discussant of the session, shared several important observations. While all of the presenters started out with a definition of endophenotypes, Nuechterlein pointed out that none of them mentioned a critical property: To qualify as an endophenotype, a candidate marker has to be state independent. Further, with recent advents in neuroimaging, Nuechterlein predicts that we will be able to identify the neural circuits underlying endophenotypes, most of which have only been characterized at the cognitive and physiological level. While a practical strategy for schizophrenia researchers would be to focus efforts on endophenotypes whose neural circuitry is better known or easier to characterize, Nuechterlein cautioned that researchers should choose them on the asis of their predictive value, for example, based on ERVs.

All presenters fondly reminisced about how Gottesman influenced them both at the scientific and personal levels. Gottesman would occasionally call them to provide detailed feedback on publications or presentations. A recurring joke was “I thought I was the only one he would call.” To that extent, David Braff talked about his admiration of Gottesman’s level of connectivity with colleagues and how he was famous for his “humor and penetrating ability to get to the point.”

An important take-home message from the symposium with respect to future directions of endophenotype research is that their developmental trajectories need to be delineated. We should 1) identify the neural circuitry underlying endophenotypes; 2) characterize the developmental trajectory of the integrity of these neural circuits; and 3) understand how one endophenotype influences another one throughout development.