Prof Jonathan Flint

Research Area: Genetics and Genomics
Technology Exchange: Bioinformatics, Chromosome mapping, Immunohistochemistry, In situ hybridisation, Medical statistics, Microscopy (Confocal), Statistical genetics, Transcript profiling and Transgenesis
Scientific Themes: Genetics & Genomics
Keywords: psychiatric, disorders, anxiety, depression, stress and genetics
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My laboratory is investigating the genetic basis of psychiatric disorders, in particular the origins of stress related conditions, such as anxiety and depression, for which we have relatively ineffective treatments. Knowing more about the biological basis of these very common disorders could help develop better therapies, and use more efficiently those we already have.
Depression and anxiety have a genetic basis, so one way to access the biology is to use genetics. The completion of the human genome project and the availability of large scale genetic resources allows to analyse the role genes play in psychiatric disorders. Because the effect attributable to a single gene is very small, genetic effects can only be detected when samples from thousands of people are analysed. In order to collect such a large sample, a surrogate measure of susceptibility to anxiety and depression was used. Neuroticism, a personality trait that is a major genetic mediator of depression, can be scored reliably and cheaply using a personality questionnaire. We have analysed over 900 families from the 26’000 questionnaires we collected.
We also use animal behaviour to help our human work. Mice show variation in the way they respond to novel environments: we can measure how much animals freeze when placed in a novel environment, and how much they explore it. We have used this to identify the genetic basis of emotional behaviour. Since much of the biology of fearfulness is common in rodents and humans, our work should help investigate human anxiety and depression.

Name Department Institution Country
Prof Richard F Mott Wellcome Trust Centre for Human Genetics Oxford University UK
Nicholas Rawlins Experimental Psychology UK
David Bannerman Experimental Psychology UK
Prof Paul Klenerman Experimental Medicine Division Oxford University UK
Christophe Benoist Joslin Institute, Harvard USA

Ahlqvist E, Ekman D, Lindvall T, Popovic M, Forster M, Hultqvist M, Klaczkowska D, Teneva I et al. 2011. High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice HUMAN MOLECULAR GENETICS, 20 (15), pp. 3031-3041. Read abstract | Read more

Resolving the genetic basis of complex diseases like rheumatoid arthritis will require knowledge of the corresponding diseases in experimental animals to enable translational functional studies. Mapping of quantitative trait loci in mouse models of arthritis, such as collagen-induced arthritis (CIA), using F crosses has been successful, but can resolve loci only to large chromosomal regions. Using an inbred-outbred cross design, we identified and fine-mapped CIA loci on a genome-wide scale. Heterogeneous stock mice were first intercrossed with an inbred strain, B10.Q, to introduce an arthritis permitting MHCII haplotype. Homozygous H2 mice were then selected to set up an F generation with fixed major histocompatibility complex that was used for arthritis experiments. We identified 26 loci, 18 of which are novel, controlling arthritis traits such as incidence of disease, severity and time of onset and fine-mapped a number of previously mapped loci. © The Author 2011. Published by Oxford University Press. All rights reserved. Hide abstract

Mathieson I, Munafò MR, Flint J. 2012. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry, 17 (6), pp. 634-641. Read abstract | Read more

Several polymorphisms in the Disrupted-in-Schizophrenia-1 (DISC1) gene are reported to be associated with schizophrenia. However, to date, there has been little effort to evaluate the evidence for association systematically. We carried out an imputation-driven meta-analysis, the most comprehensive to date, using data collected from 10 candidate gene studies and three genome-wide association studies containing a total of 11 626 cases and 15 237 controls. We tested 1241 single-nucleotide polymorphisms in total, and estimated that our power to detect an effect from a variant with minor allele frequency >5% was 99% for an odds ratio of 1.5 and 51% for an odds ratio of 1.1. We find no evidence that common variants at the DISC1 locus are associated with schizophrenia. Hide abstract

Tian T, Li Y, Xie D, Shen Y, Ren J, Wu W, Guan C, Zhang Z et al. 2012. Clinical features and risk factors for post-partum depression in a large cohort of Chinese women with recurrent major depressive disorder JOURNAL OF AFFECTIVE DISORDERS, 136 (3), pp. 983-987. | Read more

Yang F, Li Y, Xie D, Shao C, Ren J, Wu W, Zhang N, Zhang Z et al. 2011. Age at onset of major depressive disorder in Han Chinese women: Relationship with clinical features and family history Journal of Affective Disorders,

Alam I, Koller DL, Sun Q, Roeder RK, Canete T, Blazquez G, Lopez-Aumatell R, Martinez-Membrives E et al. 2011. Heterogeneous stock rat: A unique animal model for mapping genes influencing bone fragility BONE, 48 (5), pp. 1169-1177. | Read more

Clarke H, Flint J, Attwood AS, Munafo MR. 2010. Association of the 5-HTTLPR genotype and unipolar depression: a meta-analysis PSYCHOLOGICAL MEDICINE, 40 (11), pp. 1767-1778. Read abstract | Read more

Background We sought to ascertain the strength of evidence for association between the 5-HTTLPR polymorphism and unipolar depression.Method We applied meta-analytic techniques to data from relevant published studies, and obtained an estimate of the likely magnitude of effect of any association. We also tested for possible publication bias, and explored the impact of various study design characteristics on the magnitude of the observed effect size.Results Meta-analysis indicated evidence of a small but statistically significant association between the 5-HTTLPR polymorphism and unipolar depression [odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03-1.12]. This remained significant when data from samples of European and East Asian ancestry were analyzed separately. In all cases there was evidence of significant between-study heterogeneity, although the observed associations were robust to the application of a random-effects framework.Conclusions Our results support the presence of a small effect of a polymorphism in the serotonin transporter promoter on susceptibility to depression. However, we caution that it is possible that the effect has an artifactual basis, rather than a biological origin. © 2010 Cambridge University Press. Hide abstract

Flint J. 2011. Mapping quantitative traits and strategies to find quantitative trait genes. Methods, 53 (2), pp. 163-174. Read abstract | Read more

In 1999 a meeting took place at the Jackson Laboratory, a large mouse research centre in Bar Harbor, Maine, to consider the value of systematically collecting phenotypes on inbred strains of mice (Paigen and Eppig (2000) [1]). The group concluded that cataloguing the extensive phenotypic diversity present among laboratory mice, and in particular providing the research community with data from cohorts of animals, phenotyped according to standardized protocols, was essential if we were to take advantage of the possibilities of mouse genetics. Beginning with the collection of basic physiological, biochemical and behavioral data on nine commonly used inbred strains, the project has expanded so that by the beginning of 2010 data for 178 strains had been collected, with 105 phenotype projects yielding over 2000 different measurements (Bogue et al. (2007) [2]. Hide abstract

Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH. 2010. VIEWPOINT Missing heritability and strategies for finding the underlying causes of complex disease NATURE REVIEWS GENETICS, 11 (6), pp. 446-450. | Read more

Braun A, Breuss M, Salzer MC, Flint J, Cowan NJ, Keays DA. 2010. Tuba8 Is Expressed at Low Levels in the Developing Mouse and Human Brain AMERICAN JOURNAL OF HUMAN GENETICS, 86 (5), pp. 819-822. | Read more

Keays DA, Cleak J, Huang G-J, Edwards A, Braun A, Treiber CD, Pidsley R, Flint J. 2010. The Role of Tuba1a in Adult Hippocampal Neurogenesis and the Formation of the Dentate Gyrus DEVELOPMENTAL NEUROSCIENCE, 32 (4), pp. 268-277. Read abstract | Read more

The multitubulin hypothesis holds that each tubulin isotype serves a unique role with respect to microtubule function. Here we investigate the role of the α-tubulin subunit Tuba1a in adult hippocampal neurogenesis and the formation of the dentate gyrus. Employing birth date labelling and immunohistological markers, we show that mice harbouring an S140G mutation in Tuba1a present with normal neurogenic potential, but that this neurogenesis is often ectopic. Morphological analysis of the dentate gyrus in adulthood revealed a disorganised subgranular zone and a dispersed granule cell layer. We have shown that these anatomical abnormalities are due to defective migration of prospero-homeobox-1-positive neurons and T-box-brain-2-positive progenitors during development. Such migratory defects may also be responsible for the cytoarchitectural defects observed in the dentate gyrus of patients with mutations in TUBA1A. Copyright © 2010 S. Karger AG, Basel. Hide abstract

Huang GJ, Smith AL, Gray DH, Cosgrove C, Singer BH, Edwards A, Sims S, Parent JM et al. 2010. A genetic and functional relationship between T cells and cellular proliferation in the adult hippocampus. PLoS Biol, 8 (12), pp. e1000561. Read abstract | Read more

Neurogenesis continues through the adult life of mice in the subgranular zone of the dentate gyrus in the hippocampus, but its function remains unclear. Measuring cellular proliferation in the hippocampus of 719 outbred heterogeneous stock mice revealed a highly significant correlation with the proportions of CD8+ versus CD4+ T lymphocyte subsets. This correlation reflected shared genetic loci, with the exception of the H-2Ea locus that had a dominant influence on T cell subsets but no impact on neurogenesis. Analysis of knockouts and repopulation of TCRα-deficient mice by subsets of T cells confirmed the influence of T cells on adult neurogenesis, indicating that CD4+ T cells or subpopulations thereof mediate the effect. Our results reveal an organismal impact, broader than hitherto suspected, of the natural genetic variation that controls T cell development and homeostasis. Hide abstract

Yalcin B, Nicod J, Bhomra A, Davidson S, Cleak J, Farinelli L, Østerås M, Whitley A et al. 2010. Commercially available outbred mice for genome-wide association studies. PLoS Genet, 6 (9), pp. e1001085. Read abstract | Read more

Genome-wide association studies using commercially available outbred mice can detect genes involved in phenotypes of biomedical interest. Useful populations need high-frequency alleles to ensure high power to detect quantitative trait loci (QTLs), low linkage disequilibrium between markers to obtain accurate mapping resolution, and an absence of population structure to prevent false positive associations. We surveyed 66 colonies for inbreeding, genetic diversity, and linkage disequilibrium, and we demonstrate that some have haplotype blocks of less than 100 Kb, enabling gene-level mapping resolution. The same alleles contribute to variation in different colonies, so that when mapping progress stalls in one, another can be used in its stead. Colonies are genetically diverse: 45% of the total genetic variation is attributable to differences between colonies. However, quantitative differences in allele frequencies, rather than the existence of private alleles, are responsible for these population differences. The colonies derive from a limited pool of ancestral haplotypes resembling those found in inbred strains: over 95% of sequence variants segregating in outbred populations are found in inbred strains. Consequently it is possible to impute the sequence of any mouse from a dense SNP map combined with inbred strain sequence data, which opens up the possibility of cataloguing and testing all variants for association, a situation that has so far eluded studies in completely outbred populations. We demonstrate the colonies' potential by identifying a deletion in the promoter of H2-Ea as the molecular change that strongly contributes to setting the ratio of CD4+ and CD8+ lymphocytes. Hide abstract

Valdar W, Holmes CC, Mott R, Flint J. 2009. Mapping in Structured Populations by Resample Model Averaging GENETICS, 182 (4), pp. 1263-1277. Read abstract | Read more

Highly recombinant populations derived from inbred lines, such as advanced intercross lines and heterogeneous stocks, can be used to map loci far more accurately than is possible with standard intercrosses. However, the varying degrees of relatedness that exist between individuals complicate analysis, potentially leading to many false positive signals. We describe a method to deal with these problems that does not require pedigree information and accounts for model uncertainty through model averaging. In our method, we select multiple quantitative trait loci (QTL) models using forward selection applied to resampled data sets obtained by nonparametric bootstrapping and subsampling. We provide model-averaged statistics about the probability of loci or of multilocus regions being included in model selection, and this leads to more accurate identification of QTL than by single-locus mapping. The generality of our approach means it can potentially be applied to any population of unknown structure. Copyright © 2009 by the Genetics Society of America. Hide abstract

Huang GJ, Shifman S, Valdar W, Johannesson M, Yalcin B, Taylor MS, Taylor JM, Mott R, Flint J. 2009. High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues. Genome Res, 19 (6), pp. 1133-1140. Read abstract | Read more

A proportion of the genetic variants underlying complex phenotypes do so through their effects on gene expression, so an important challenge in complex trait analysis is to discover the genetic basis for the variation in transcript abundance. So far, the potential of mapping both quantitative trait loci (QTLs) and expression quantitative trait loci (eQTLs) in rodents has been limited by the low mapping resolution inherent in crosses between inbred strains. We provide a megabase resolution map of thousands of eQTLs in hippocampus, lung, and liver samples from heterogeneous stock (HS) mice in which 843 QTLs have also been mapped at megabase resolution. We exploit dense mouse SNP data to show that artifacts due to allele-specific hybridization occur in approximately 30% of the cis-acting eQTLs and, by comparison with exon expression data, we show that alternative splicing of the 3' end of the genes accounts for <1% of cis-acting eQTLs. Approximately one third of cis-acting eQTLs and one half of trans-acting eQTLs are tissue specific. We have created an important systems biology resource for the genetic analysis of complex traits in a key model organism. Hide abstract

Flint J, Mackay TF. 2009. Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res, 19 (5), pp. 723-733. Read abstract | Read more

We compare and contrast the genetic architecture of quantitative phenotypes in two genetically well-characterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, with that found in our own species from recent successes in genome-wide association studies. We show that the current model of large numbers of loci, each of small effect, is true for all species examined, and that discrepancies can be largely explained by differences in the experimental designs used. We argue that the distribution of effect size of common variants is the same for all phenotypes regardless of species, and we discuss the importance of epistasis, pleiotropy, and gene by environment interactions. Despite substantial advances in mapping quantitative trait loci, the identification of the quantitative trait genes and ultimately the sequence variants has proved more difficult, so that our information on the molecular basis of quantitative variation remains limited. Nevertheless, available data indicate that many variants lie outside genes, presumably in regulatory regions of the genome, where they act by altering gene expression. As yet there are very few instances where homologous quantitative trait loci, or quantitative trait genes, have been identified in multiple species, but the availability of high-resolution mapping data will soon make it possible to test the degree of overlap between species. Hide abstract

Munafo MR, Durrant C, Lewis G, Flint J. 2009. Gene x Environment Interactions at the Serotonin Transporter Locus BIOLOGICAL PSYCHIATRY, 65 (3), pp. 211-219. Read abstract | Read more

Background: Although it is universally accepted that human disease and behavior depend upon both environmental and genetic variation, a view supported by family and twin studies, examples of environmental interactions with genes identified at the molecular level (G × E) are not so well established. Methods: We carried out a systematic review and meta-analysis of the serotonin transporter (5-HTTLPR) polymorphic region × stressful life event (SLE) literature and investigated to what extent the main effects reported in this literature are consistent with a number of G × E hypotheses. Our aim was to provide a framework in which to assess the robustness of the claim for the presence of an interaction. Results: The results from our systematic review and meta-analysis indicate that the main effect of 5-HTTLPR genotype and the interaction effect between 5-HTTLPR and SLE on risk of depression are negligible. We found that only a minority of studies report a replication that is qualitatively comparable to that in the original report. Conclusions: Given reasonable assumptions regarding likely genetic and environmental effect sizes, our simulations indicate that published studies are underpowered. This, together with other aspects of the literature, leads us to suggest that the positive results for the 5-HTTLPR × SLE interactions in logistic regression models are compatible with chance findings. © 2009 Society of Biological Psychiatry. Hide abstract

Flint J, Munafò MR. 2007. The endophenotype concept in psychiatric genetics. Psychol Med, 37 (2), pp. 163-180. Read abstract | Read more

The idea that some phenotypes bear a closer relationship to the biological processes that give rise to psychiatric illness than diagnostic categories has attracted considerable interest. Much effort has been devoted to finding such endophenotypes, partly because it is believed that the genetic basis of endophenotypes will be easier to analyse than that of psychiatric disease. This belief depends in part on the assumption that the effect sizes of genetic loci contributing to endophenotypes are larger than those contributing to disease susceptibility, hence increasing the chance that genetic linkage and association tests will detect them. We examine this assumption by applying meta-analytical techniques to genetic association studies of endophenotypes. We find that the genetic effect sizes of the loci examined to date are no larger than those reported for other phenotypes. A review of the genetic architecture of traits in model organisms also provides no support for the view that the effect sizes of loci contributing to phenotypes closer to the biological basis of disease is any larger than those contributing to disease itself. While endophenotype measures may afford greater reliability, it should not be assumed that they will also demonstrate simpler genetic architecture. Hide abstract

Keays DA, Tian G, Poirier K, Huang GJ, Siebold C, Cleak J, Oliver PL, Fray M et al. 2007. Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell, 128 (1), pp. 45-57. Read abstract | Read more

The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of alpha-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders. Hide abstract

Shifman S, Bell JT, Copley RR, Taylor MS, Williams RW, Mott R, Flint J. 2006. A high-resolution single nucleotide polymorphism genetic map of the mouse genome. PLoS Biol, 4 (12), pp. e395. Read abstract | Read more

High-resolution genetic maps are required for mapping complex traits and for the study of recombination. We report the highest density genetic map yet created for any organism, except humans. Using more than 10,000 single nucleotide polymorphisms evenly spaced across the mouse genome, we have constructed genetic maps for both outbred and inbred mice, and separately for males and females. Recombination rates are highly correlated in outbred and inbred mice, but show relatively low correlation between males and females. Differences between male and female recombination maps and the sequence features associated with recombination are strikingly similar to those observed in humans. Genetic maps are available from http://gscan.well.ox.ac.uk/#genetic_map and as supporting information to this publication. Hide abstract

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 (8), pp. 879-887. Read abstract | Read more

Difficulties in fine-mapping quantitative trait loci (QTLs) are a major impediment to progress in the molecular dissection of complex traits in mice. Here we show that genome-wide high-resolution mapping of multiple phenotypes can be achieved using a stock of genetically heterogeneous mice. We developed a conservative and robust bootstrap analysis to map 843 QTLs with an average 95% confidence interval of 2.8 Mb. The QTLs contribute to variation in 97 traits, including models of human disease (asthma, type 2 diabetes mellitus, obesity and anxiety) as well as immunological, biochemical and hematological phenotypes. The genetic architecture of almost all phenotypes was complex, with many loci each contributing a small proportion to the total variance. Our data set, freely available at http://gscan.well.ox.ac.uk, provides an entry point to the functional characterization of genes involved in many complex traits. Hide abstract

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 (11), pp. 1197-1202. Read abstract | Read more

Here we present a strategy to determine the genetic basis of variance in complex phenotypes that arise from natural, as opposed to induced, genetic variation in mice. We show that a commercially available strain of outbred mice, MF1, can be treated as an ultrafine mosaic of standard inbred strains and accordingly used to dissect a known quantitative trait locus influencing anxiety. We also show that this locus can be subdivided into three regions, one of which contains Rgs2, which encodes a regulator of G protein signaling. We then use quantitative complementation to show that Rgs2 is a quantitative trait gene. This combined genetic and functional approach should be applicable to the analysis of any quantitative trait. Hide abstract