Winners of 2009 ICOSR Essay Contest!

Ian Kelleher

Carrie Bearden

Congratulations are in order for the two winners of the 2009 ICOSR Contest—Ian Kelleher, Royal College of Surgeons, Ireland, and Carrie Bearden, University of California, Los Angeles. Each winner gets one free registration and four nights’ hotel stay at the 2009 International Congress on Schizophrenia Research. We have posted their winning essays in response to the question, "How can we combine different approaches to achieve a mechanistic understanding of schizophrenia?"

Ian Kelleher, Royal College of Surgeons, Ireland

Research has shown that psychotic-type experiences occur not just in psychotic disorders (disease phenotype), but also among a substantial portion of the general population (non-clinical psychosis phenotype). A number of studies have now demonstrated that children who report psychotic-type experiences are at increased risk of clinical psychotic disorders. Poulton et al. (2000) found that, among a New Zealand birth cohort, there was a five- to 16-fold increased risk of clinical psychotic disorder by age 26 for study participants who had reported psychotic-type symptoms during adolescence. Hanssen et al. (2005) found that the two-year transition rate to clinical psychotic disorder was more than 60 times higher for those who had previously reported psychotic-type experiences. Adolescents who report psychotic-type experiences, then, represent a valuable population in studying the developmental trajectory to schizophrenia and related illnesses.

Given that this population can provide us with unique insights into the development of schizophrenia, a number of research groups are studying developmental differences between adolescents with the non-clinical psychosis phenotype compared with the rest of the population. For example, Laurens et al. (2007) have reported on speech and motor development lags and social, emotional, and behavioral problems among this population with a view to (ultimately) understanding how developmental problems may contribute to the conversion from a non-clinical phenotype to clinical psychosis. While developmental work such as this is of great value, advancements in the understanding of genetic contributions to schizophrenia may also lie in this approach.

Vast amounts of research have been conducted to investigate genetic contributions to schizophrenia. The limited genetic findings in schizophrenia to date, however, may be confounded by shared genetic variation between the clinical (disease) phenotype and the non-clinical phenotype, especially since the latter phenotype is much more common than the former. It may be the case that genetic risk for schizophrenia lies in the development of the non-clinical phenotype. Conversion from non-clinical to disease phenotype among this group may be accounted for by non-genetic factors. Thus, rather than searching for genetic variation between 1) individuals with psychotic disorders and 2) the rest of the population (which includes vast numbers of individuals with a non-clinical psychosis phenotype), it may prove more fruitful to investigate genetic variation using the following two different groups: a) individuals with the non-clinical psychosis phenotype (plus or minus individuals with the disease phenotype) and b) the rest of the population with no psychosis phenotype (clinical or non-clinical).

References:
Laurens KR, Hodgins S, Maughan B, Murray RM, Rutter ML, Taylor EA (2007) Community screening for psychotic-like experiences and other putative antecedents of schizophrenia in children aged 9-12 years. Schizophrenia Research, 90: 130–146. Abstract

Poulton R, Caspi A, Moffitt TE, Cannon M, Murray RM, Harrington H (2000) Children's self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study. Archives of General Psychiatry, 57: 1053-1058. Abstract

Hanssen M, Bak M, Bijl R, Vollebergh and van Os J (2005) The incidence and outcome of subclinical psychotic experiences in the general population. British Journal of Clinical Psychology, 44: 181-191. Abstract

Carrie Bearden, University of California, Los Angeles

Although schizophrenia is a highly heritable, biologically based illness, its complexity and heterogeneity poses an enormous challenge to biomedical discovery. Current classification schemas are based on particular clusters of symptoms and clinical course descriptors that do not necessarily describe homogeneous conditions, but rather reflect final common pathways of various pathophysiological processes. At the same time, the same disease phenotype can potentially be caused by mutations in different genetic loci (locus heterogeneity) (Lin and Biswas, 2004), which poses a major obstacle for mapping genes that influence complex genetic traits. Indeed, newly emerging evidence suggests that rare genetic mutations that disrupt neurodevelopmental pathways may play a larger role in psychotic illness than was previously believed. For example, microdeletions of chromosome 22q11.2 account for up to 1-2 percent of schizophrenia cases (Stark et al., 2008). Recently, both microdeletions and duplications on chromosome 15q11.2-13.3, which extends across the Prader-Willi/Angelman syndrome critical locus, have also been associated with schizophrenia in multiple studies (Need et al., 2009).

As such, I believe that the multilevel investigation of rare genetic variants of large effect can yield unique biological insight into the mechanisms underlying the development of schizophrenia. This “behavioral neurogenetics” approach allows us to investigate the way in which a well-characterized genetic anomaly can lead to a cascade of abnormal neurodevelopmental processes, which disrupt brain structure and function, and manifest as disturbances of emotion, cognition, and behavior that are ultimately classified as "schizophrenia" (Reiss et al., 2000). “Deep phenotyping” at the level of brain structure and function, neurocognitive assays, and dimensional measures of psychopathology and behavior in these individuals with rare genetic events are, I strongly believe, the best way to move research forward.

References:
Lin S, Biswas S. On modeling locus heterogeneity using mixture distributions. BMC Genet. Sep 30 2004;5:29. Abstract

Stark KL, Xu B, Bagchi A, et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. Jun 2008;40(6):751-760. Abstract

Need AC, Ge D, et al. A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia. PLoS Genet. 2009 Feb;5(2):e1000373. Epub 2009 Feb 6. Abstract

Reiss AL, Eliez S, Schmitt JE, Patwardhan A, Haberecht M. Brain imaging in neurogenetic conditions: realizing the potential of behavioral neurogenetics research. Ment Retard Dev Disabil Res Rev. 2000;6(3):186-197. Abstract