Fullerton, J.M., et al. Human-mouse quantitative trait locus concordance and the dissection of a human neuroticism locus.
Biol Psychiatry 63, 874-83 (2008).
AbstractBACKGROUND: Exploiting synteny between mouse and human disease loci has been proposed as a cost-effective method for the identification of human susceptibility genes. Here we explore its utility in an analysis of a human personality trait, neuroticism, which can be modeled in mice by tests of emotionality. We investigated a mouse emotionality locus on chromosome 1 that contains no annotated genes but abuts four regulators of G protein signaling, one of which (rgs2) has been previously identified as a quantitative trait gene for emotionality. This locus is syntenic with a human region that has been consistently implicated in the genetic aetiology of neuroticism.
METHODS: The functional candidacy of 29 murine sequence variants was tested by a combination of gel shift and transient transfection assays. Murine sequences that contained functional variants and exhibited significant cross-species conservation were prioritized for investigation in humans. Genetic association with neuroticism was tested in 1869 high and 2032 low unrelated individuals scored for neuroticism, selected from the extremes of 88,141 people from southwest England.
RESULTS: Fifteen sequence variants contributed to variation in the expression of rgs18, the gene lying at the edge of the quantitative trait loci (QTL) interval. There was no evidence of association between neuroticism and single nucleotide polymorphisms (SNPs) lying in the human regions homologous to those of mouse functional variants. One SNP, rs6428058, in a region of sequence conservation 644 kb upstream of RGS18, showed significant association (p = .000631).
CONCLUSIONS: It is unlikely that a single variant is responsible for the mouse emotionality locus on chromosome 1. This level of underlying genetic complexity means that although cross-species QTL concordance may be invaluable for the identification of human disease loci, it is unlikely to be as informative in the identification of human disease-causing variants.
Flint, J. & Shifman, S. Animal models of psychiatric disease.
Curr Opin Genet Dev 18, 235-40 (2008).
AbstractAnimal models of psychiatric diseases are useful tools for screening new drugs and for investigating the mechanisms of those disorders. Despite the difficulties inherent in modelling human psychiatric phenotypes in animals, there has been recent success identifying mutations in mice that give rise to some of the characteristic features of anxiety, depression, schizophrenia, autism, obsessive-compulsive disorder and bipolar disorder. In some cases these models have the additional strength that drugs used to treat the human condition alleviate the symptoms in mice. Robust genetic evidence of the involvement of multiple susceptibility genes in psychiatric disease will enable future studies to move from single-gene models to models with multiple modified loci, with the promise of better representing the complexity of the human diseases.
Flint, J., Shifman, S., Munafo, M. & Mott, R. Genetic variants in major depression.
Novartis Found Symp 289, 23-32; discussion 33-42, 87-93 (2008).
AbstractMajor depression is one of the most common and most debilitating disorders in the world. A wealth of data indicate that additive genetic effects contribute to at least 30% of the variance in liability to major depression, yet attempts to identify the molecular basis of susceptibility using standard family based linkage and genetic association methodologies have had limited success. Alternative approaches have recently been advocated, such as the inclusion of gene by environment interactions and the use of endophenotypes. Our own data indicate that the genetic architecture of affective illness is more complex than expected. A whole genome association study of neuroticism, a personality trait that shares many of the same susceptibility loci as depression, reveals that the individual effect sizes are less than 1%. Larger sample sizes and more sophisticated analytical approaches will be needed than have hitherto been applied.
O'Donovan, M.C., et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up.
Nat Genet 40, 1053-5 (2008).
AbstractWe carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).
Falkai, P., et al. A roadmap to disentangle the molecular etiology of schizophrenia.
Eur Psychiatry 23, 224-32 (2008).
AbstractSchizophrenia is a severe mental disorder striking mainly young adults and leading to life-long disability in a substantial portion of the sufferers. On the other hand, substantial knowledge about its etiology and pathogenesis is still lacking. Therefore the European Science Foundation (ESF) sponsored a meeting of a panel of European experts on schizophrenia research to discuss the state of art and future perspectives of key topics in this area. The fields covered genetics, epidemiology, animal models, molecular neuropathology and imaging. This was a first step to establish a network of European groups dedicated to Schizophrenia research. The coming calls of the frame work program will be used to strengthen this network in order to achieve substantial progress in understanding and treating this devastating illness.