Professor Jonathan Flint is Head of the Psychiatric Genetics Group at the Wellcome Trust Centre for Human Genetics (WTCHG).
Genetics of common psychiatric disorders
Mouse models of complex traits
In an entirely separate body of work, I have published seminal papers on working with mouse models to identify genes that determine behavioural traits. Together with my colleague Richard Mott, I have developed an entirely novel methodology for finding genes involved in complex traits in the mouse. We have shown that it is possible to use the genetic diversity present in outbred mice to map variation in complex traits, including disease models. We were the first to mount a genome-wide association study in any species (Nature Genetics 2006). This approach led to the first identification of a gene involved in behaviour whose effect is mediated by a naturally-occurring sequence variant (Nature Genetics 2004). Furthermore, by exploiting the genetic architecture of outbred stocks we have shown that it is possible to associate specific sequence variants with phenotypes (Genetics 2005). When combined with next-generation sequencing, this means it is possible to detect all variants that have an effect on a complex phenotype such as behaviour with consequent insights into the genetic architecture of the phenotype (Nature 2011). These approaches have revealed that cofilin-1 is involved in mouse models of anxiety.
In a classic instance of how mouse genetic approaches can be used to understand the cause of human disease, I identified a mutation in alpha tubulin as a cause of neuronal migration defects in mouse and in humans. The tubulins would never have been considered candidates in human genetics had it not been for the pioneering mouse work. The human condition, lissencephaly, is a disabling disorder characterized by severe intellectual disability and a characteristic anatomical defect in which the sulci and gyri of the brain are almost absent (hence the condition is sometimes called ‘smooth brain’). Surprisingly the same mutation in the mouse manifests as hyperactivity with relatively little impact on cognition. However, mutants in both species give rise to the same pathology: abnormal neuronal migration. This work, published in Cell in 2007, shows the power of using mouse genetics to investigate disease pathogenesis (Keays et al 2007).
My first major body of research is related to investigating causes of cognitive impairment. A decade before data came from the Human Genome Project, I showed for the first time that cryptic chromosome rearrangements are responsible for intellectual disability in humans. A follow-up paper provided further data to support the these findings and helped revolutionise the way we now regard idiopathic cognitive disability, directly and indirectly resulting in several new ‘large-science’ screening efforts to discover the many causes of mental retardation. In addition, and unusually for a basic science investigation, this work directly provided the molecular reagents for a test suitable for clinical application, which then showed that small rearrangements involving the ends of chromosomes are detectable in approximately 8% of people with mental retardation of unknown aetiology (cryptic sub-telomeric abnormalities are thus the second most common cause of mental retardation after Down Syndrome). The work has impacted directly on clinical services and influenced subsequent whole genome analyses for small rearrangements and copy number variants.
The Wellcome Trust