Professor Jonathan Flint is Head of the Psychiatric Genetics Group at the Wellcome Trust Centre for Human Genetics (WTCHG).
Anxiety and depression
My laboratory investigates the genetic basis of common psychiatric disorders, in particular the determination of the genetic basis of anxiety and depression in animal models and in humans. I have used two complementary approaches in the investigation of emotional disorders.
(i) Animal models
I use animal models to identify genetic factors underlying anxiety and depression. I was the first to show that the genetic basis of an animal model of human anxiety is amenable to mapping (Flint et al. 1995a). Since then I have developed novel strategies for fine-mapping quantitative trait loci (QTL) using outbred animals. I was the first to propose the use of outbred heterogeneous stocks for genetic mapping, and have gone on to develop the methodology that makes the identification of susceptibility genes possible using this approach(Mott et al. 2000; Talbot et al. 1999). Using a novel analytical approach (ancestral probabilistic haplotype reconstruction) and a gene knock-out interaction test, my group mapped and cloned a gene at a QTL influencing susceptibility to anxiety in mice (Yalcin et al. 2004). On the basis of this success I have gone on to apply the fine-mapping method to a whole-genome analysis of multiple phenotypes.
In collaboration with other groups in Oxford I have now mapped QTLs influencing susceptibility to asthma, type II diabetes and obesity, as well as behaviour. Overall, the project identified more than 800 QTLs, each mapped to intervals of about 3 megabases, at which point gene identification becomes feasible (Valdar et al. 2006). Using heterogeneous stock mice I am beginning to generate novel insights into the biological basis of anxiety and depression. A recent insight of note has been the unexpected discovery that adult neurogenesis, believed to be involved in anxiety and depression, has a closer genetic (and hence functional) relationship to the immune system than to behavioural phenotypes(Huang et al. 2010).
I am currently developing methods that will make straightforward the identification of the relevant genes in mice. This has led to the genetic characterization of outbred stocks, the realization that they can deliver gene level resolution(Yalcin et al. 2010) , and to a fuller understanding of the value of complete genome sequence. Using next generation sequencing I have coordinated a project to obtain genome sequence of 17 inbred strains of mice. The results were published in two articles in Nature(Yalcin et al. 2011).
(ii) Human studies
I have been mapping anxiety and depression in humans. I was the first to map the genetic basis of neuroticism, a personality trait that is genetically correlated with both depression and generalized anxiety disorder(Fullerton et al. 2003). My work showed the complexity of the genetic basis and led to a series of highly cited publications demonstrating the inadequacies of candidate gene studies in psychiatry (Flint & Munafo 2007; Mathieson et al. 2011; Willis-Owen et al. 2005).
In the last three years I have undertaken the largest project of its kind anwhere in the world in the genetics of major depression. In collaboration with 60 hospitals across China I have obtained now 4,500 cases and 5,000 controls, all carefully phenotyped and ready for whole genome sequencing. Initial results from this work are now in press, in a series of 11 articles in psychiatric journals. These findings are already generating considerable interest. When the genetic analysis is complete, some time next year, we will be able to make a major advance in understanding the biological basis of the commonest of all psychiatric illnesses.
I have investigated the causes of idiopathic mental retardation, a common condition that, when I began my work, was relatively under-researched. I asked whether newly available molecular tools could be used to detect small chromosomal rearrangements in children and adults with learning disabilities. My work showed that small rearrangements involving the ends of chromosomes are detectable in approximately 8% of people with mental retardation of unknown aetiology (Flint et al. 1995b; Knight et al. 1999). This makes cryptic sub-telomeric abnormalities the second most common cause of mental retardation after Down Syndrome. The test I have developed has been widely adopted throughout the world in clinical genetics centres. Furthermore, by characterizing the ends of human chromosomes, my investigations led to the first sequence map of a human telomere and advanced understanding of the relationship between chromosome structure and function(Flint et al. 1997; National Institutes of Health et al. 1996).
My work on mental retardation has continued through screening mutant mice for abnormalties that might explain human conditions. This strategy successfully identified tubulin genes as important loci that give rise to neuronal migration disorders such as lissencephaly (Keays et al. 2007).
My original training in molecular genetics took place at the MRC molecular haematology unit in Oxford, where I demonstrated that selection by malaria explains why alpha thalassaemia (an inherited disorder of haemoglobin synthesis) is the commonest Mendelian genetic disorder in the world. This epidemiological work, published in Nature in 1984, is still one of the best examples of the effects of selection on gene frequencies in human populations(Flint et al. 1986).
Flint J, Corley R, DeFries JC, Fulker DW, Gray JA, Miller S, Collins AC (1995a). A simple genetic basis for a complex psychological trait in laboratory mice. Science 269, 1432-5.
Flint J, Hill AV, Bowden DK, Oppenheimer SJ, Sill PR, Serjeantson SW, Bana Koiri J, Bhatia K, Alpers MP, Boyce AJ, et al. (1986). High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature 321, 744-50.
Flint J, Munafo MR (2007). The endophenotype concept in psychiatric genetics. Psychol Med 37, 163-80.
Flint J, Thomas K, Micklem G, Raynham H, Clark K, Doggett NA, King A, Higgs DR (1997). The relationship between chromosome structure and function at a human telomeric region. Nature Genetics 15, 252-257.
Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE (1995b). The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nature Genetics 9, 132-40.
Fullerton J, Cubin M, Tiwari H, Wang C, Bomhra A, Davidson S, Miller S, Fairburn C, Goodwin G, Neale MC, Fiddy S, Mott R, Allison DB, Flint J (2003). Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait Loci that influence variation in the human personality trait neuroticism. Am J Hum Genet 72, 879-90.
Huang GJ, Smith AL, Gray DH, Cosgrove C, Singer BH, Edwards A, Sim S, Parent JM, Johnsen A, Mott R, Mathis D, Klenerman P, Benoist C, Flint J (2010). A genetic and functional relationship between T cells and cellular proliferation in the adult hippocampus. PLoS Biol 8, e1000561.
Keays DA, Tian G, Poirier K, Huang GJ, Siebold C, Cleak J, Oliver PL, Fray M, Harvey RJ, Molnar Z, Pinon MC, Dear N, Valdar W, Brown SD, Davies KE, Rawlins JN, Cowan NJ, Nolan P, Chelly J, Flint J (2007). Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128, 45-57.
Knight SJL, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, Winter RM, Bolton P, Flint J (1999). Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 354, 1676-1681.
Mathieson I, Munafo MR, Flint J (2011). Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry.
Mott R, Talbot CJ, Turri MG, Collins AC, Flint J (2000). A method for fine mapping quantitative trait loci in outbred animal stocks. Proc Natl Acad Sci U S A 97, 12649-54.
National Institutes of Health, Institute of Molecular Medicine Collaboration, Ning Y, Roschke A, Smith AC, Macha M, Precht K, Riethman H, Ledbetter D, Flint J, Horsley S, Regan R, Kearney K, Knight S, Kvaloy K, Brown WRA (1996). A complete set of human telomeric probes and their clinical application. Nature Genetics 14, 86-89.
Talbot CJ, Nicod A, Cherny SS, Fulker DW, Collins AC, Flint J (1999). High-resolution mapping of quantitative trait loci in outbred mice. Nature Genetics 21, 305-308.
Valdar W, Solberg LC, Gauguier D, Burnett S, Klenerman P, Cookson WO, Taylor MS, Rawlins JN, Mott R, Flint J (2006). Genome-wide genetic association of complex traits in heterogeneous stock mice. Nat Genet 38, 879-87.
Willis-Owen SA, Turri MG, Munafo MR, Surtees PG, Wainwright NW, Brixey RD, Flint J (2005). The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry 58, 451-6.
Yalcin B, Nicod J, Bhomra A, Davidson S, Cleak J, Farinelli L, Osteras M, Whitley A, Yuan W, Gan X, Goodson M, Klenerman P, Satpathy A, Mathis D, Benoist C, Adams DJ, Mott R, Flint J (2010). Commercially available outbred mice for genome-wide association studies. PLoS Genet 6.
Yalcin B, Willis-Owen SA, Fullerton J, Meesaq A, Deacon RM, Rawlins JN, Copley RR, Morris AP, Flint J, Mott R (2004). Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nat Genet 36, 1197-202.
Yalcin B, Wong K, Agam A, Goodson M, Keane TM, Gan X, Nellaker C, Goodstadt L, Nicod J, Bhomra A, Hernandez-Pliego P, Whitley H, Cleak J, Dutton R, Janowitz D, Mott R, Adams DJ, Flint J (2011). Sequence-based characterization of structural variation in the mouse genome. Nature 477, 326-9.
The Wellcome Trust
Neurogenetics Anxiety Depression Psychiatric Genetics