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

Yang F, Zhao H, Wang Z, Tao D, Xiao X, Niu Q, Wang Q, Li Y et al. 2014. Age at onset of recurrent major depression in Han Chinese women - a replication study. J Affect Disord, 157 pp. 72-79. Read abstract | Read more

The relationship between age at onset (AAO) and major depression (MD) has been studied in US, European and Chinese populations. However, larger sample studies are needed to replicate and extend earlier findings. Hide abstract

Yang F, Qiu J, Zhao H, Wang Z, Tao D, Xiao X, Niu Q, Wang Q et al. 2014. The prevalence, clinical correlates and structure of phobic fears in Han Chinese women with recurrent major depression. J Affect Disord, 157 pp. 92-99. Read abstract | Read more

Phobic fears are common in the general population and among individuals with major depression (MD). We know little about the prevalence, clinical correlates, and structure of phobic fears in Chinese women with MD. Hide abstract

Flint J, Kendler KS. 2014. The genetics of major depression. Neuron, 81 (3), pp. 484-503. Read abstract | Read more

Major depression is the commonest psychiatric disorder and in the U.S. has the greatest impact of all biomedical diseases on disability. Here we review evidence of the genetic contribution to disease susceptibility and the current state of molecular approaches. Genome-wide association and linkage results provide constraints on the allele frequencies and effect sizes of susceptibility loci, which we use to interpret the voluminous candidate gene literature. We consider evidence for the genetic heterogeneity of the disorder and the likelihood that subtypes exist that represent more genetically homogenous conditions than have hitherto been analyzed. Hide abstract

Tuncel J, Haag S, Yau AC, Norin U, Baud A, Lönnblom E, Maratou K, Ytterberg AJ et al. 2014. Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat. PLoS Genet, 10 (2), pp. e1004151. Read abstract | Read more

Genetic variation in the major histocompatibility complex (MHC) affects CD4∶CD8 lineage commitment and MHC expression. However, the contribution of specific genes in this gene-dense region has not yet been resolved. Nor has it been established whether the same genes regulate MHC expression and T cell selection. Here, we assessed the impact of natural genetic variation on MHC expression and CD4∶CD8 lineage commitment using two genetic models in the rat. First, we mapped Quantitative Trait Loci (QTLs) associated with variation in MHC class I and II protein expression and the CD4∶CD8 T cell ratio in outbred Heterogeneous Stock rats. We identified 10 QTLs across the genome and found that QTLs for the individual traits colocalized within a region spanning the MHC. To identify the genes underlying these overlapping QTLs, we generated a large panel of MHC-recombinant congenic strains, and refined the QTLs to two adjacent intervals of ∼0.25 Mb in the MHC-I and II regions, respectively. An interaction between these intervals affected MHC class I expression as well as negative selection and lineage commitment of CD8 single-positive (SP) thymocytes. We mapped this effect to the transporter associated with antigen processing 2 (Tap2) in the MHC-II region and the classical MHC class I gene(s) (RT1-A) in the MHC-I region. This interaction was revealed by a recombination between RT1-A and Tap2, which occurred in 0.2% of the rats. Variants of Tap2 have previously been shown to influence the antigenicity of MHC class I molecules by altering the MHC class I ligandome. Our results show that a restricted peptide repertoire on MHC class I molecules leads to reduced negative selection of CD8SP cells. To our knowledge, this is the first study showing how a recombination between natural alleles of genes in the MHC influences lineage commitment of T cells. Hide abstract

Mott R, Yuan W, Kaisaki P, Gan X, Cleak J, Edwards A, Baud A, Flint J. 2014. The architecture of parent-of-origin effects in mice. Cell, 156 (1-2), pp. 332-342. Read abstract | Read more

The number of imprinted genes in the mammalian genome is predicted to be small, yet we show here, in a survey of 97 traits measured in outbred mice, that most phenotypes display parent-of-origin effects that are partially confounded with family structure. To address this contradiction, using reciprocal F1 crosses, we investigated the effects of knocking out two nonimprinted candidate genes, Man1a2 and H2-ab1, that reside at nonimprinted loci but that show parent-of-origin effects. We show that expression of multiple genes becomes dysregulated in a sex-, tissue-, and parent-of-origin-dependent manner. We provide evidence that nonimprinted genes can generate parent-of-origin effects by interaction with imprinted loci and deduce that the importance of the number of imprinted genes is secondary to their interactions. We propose that this gene network effect may account for some of the missing heritability seen when comparing sibling-based to population-based studies of the phenotypic effects of genetic variants. Hide abstract

Huang GJ, Edwards A, Tsai CY, Lee YS, Peng L, Era T, Hirabayashi Y, Tsai CY et al. 2014. Ectopic cerebellar cell migration causes maldevelopment of Purkinje cells and abnormal motor behaviour in Cxcr4 null mice. PLoS One, 9 (2), pp. e86471. Read abstract | Read more

SDF-1/CXCR4 signalling plays an important role in neuronal cell migration and brain development. However, the impact of CXCR4 deficiency in the postnatal mouse brain is still poorly understood. Here, we demonstrate the importance of CXCR4 on cerebellar development and motor behaviour by conditional inactivation of Cxcr4 in the central nervous system. We found CXCR4 plays a key role in cerebellar development. Its loss leads to defects in Purkinje cell dentritogenesis and axonal projection in vivo but not in cell culture. Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion. Consistent with functional impairment of the cerebellum, Cxcr4 knockout mice have poor coordination and balance performance in skilled motor tests. Together, these results suggest ectopic the migration of granule cells impairs development of Purkinje cells, causes gross cerebellar anatomical disruption and leads to behavioural motor defects in Cxcr4 null mice. Hide abstract

Chen J, Cai Y, Cong E, Liu Y, Gao J, Li Y, Tao M, Zhang K et al. 2014. Childhood sexual abuse and the development of recurrent major depression in Chinese women. PLoS One, 9 (1), pp. e87569. Read abstract | Read more

Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set? Hide abstract

Shi J, Zhang Y, Liu F, Li Y, Wang J, Flint J, Gao J, Li Y et al. 2014. Associations of educational attainment, occupation, social class and major depressive disorder among Han Chinese women. PLoS One, 9 (1), pp. e86674. Read abstract | Read more

The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years. Hide abstract

Button KS, Mokrysz C, Munafò MR, Ioannidis JPA, Nosek BA, Flint J, Robinson ESJ. 2013. Empirical evidence for low reproducibility indicates low pre-study odds Nature Reviews Neuroscience, 14 (12), pp. 877-877. | Read more

Zhu Y, Zhang H, Shi S, Gao J, Li Y, Tao M, Zhang K, Wang X et al. 2013. Suicidal risk factors of recurrent major depression in Han Chinese women. PLoS One, 8 (11), pp. e80030. Read abstract | Read more

The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of melancholia, and earlier age of onset. Comorbidity with dysthymia, generalized anxiety disorder (GAD), social phobia, and animal phobia was seen in suicidal patients. The present findings indicate that specific factors act to increase the likelihood of suicide in MD. Our results may help improve the clinical assessment of suicide risk in depressed patients, especially for women. Hide abstract

Wang L, Liu L, Shi S, Gao J, Liu Y, Li Y, Zhang Z, Wang G et al. 2013. Cognitive trio: relationship with major depression and clinical predictors in Han Chinese women. Psychol Med, 43 (11), pp. 2265-2275. Read abstract | Read more

Previous studies support Beck's cognitive model of vulnerability to depression. However, the relationship between his cognitive triad and other clinical features and risk factors among those with major depression (MD) has rarely been systematically studied. Hide abstract

Groves JO, Leslie I, Huang GJ, McHugh SB, Taylor A, Mott R, Munafò M, Bannerman DM, Flint J. 2013. Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic model. PLoS Genet, 9 (9), pp. e1003718. Read abstract | Read more

The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis. Hide abstract

Li Y, Aggen S, Shi S, Gao J, Li Y, Tao M, Zhang K, Wang X et al. 2013. The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women. Psychol Med, pp. 1-11. Read abstract | Read more

The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome? Method Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples. Hide abstract

Hosseini M, Goodstadt L, Hughes JR, Kowalczyk MS, de Gobbi M, Otto GW, Copley RR, Mott R, Higgs DR, Flint J. 2013. Causes and consequences of chromatin variation between inbred mice. PLoS Genet, 9 (6), pp. e1003570. Read abstract | Read more

Variation at regulatory elements, identified through hypersensitivity to digestion by DNase I, is believed to contribute to variation in complex traits, but the extent and consequences of this variation are poorly characterized. Analysis of terminally differentiated erythroblasts in eight inbred strains of mice identified reproducible variation at approximately 6% of DNase I hypersensitive sites (DHS). Only 30% of such variable DHS contain a sequence variant predictive of site variation. Nevertheless, sequence variants within variable DHS are more likely to be associated with complex traits than those in non-variant DHS, and variants associated with complex traits preferentially occur in variable DHS. Changes at a small proportion (less than 10%) of variable DHS are associated with changes in nearby transcriptional activity. Our results show that whilst DNA sequence variation is not the major determinant of variation in open chromatin, where such variants exist they are likely to be causal for complex traits. Hide abstract

Rat Genome Sequencing and Mapping Consortium, Baud A, Hermsen R, Guryev V, Stridh P, Graham D, McBride MW, Foroud T et al. 2013. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet, 45 (7), pp. 767-775. Read abstract | Read more

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species. Hide abstract

Button KS, Ioannidis JPA, Mokrysz C, Nosek BA, Flint J, Robinson ESJ, Munafò MR. 2013. Power failure: why small sample size undermines the reliability of neuroscience Nature Reviews Neuroscience, 14 (5), pp. 365-376. Read abstract | Read more

A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles. © 2013 Macmillan Publishers Limited. All rights reserved. Hide abstract

Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, Munafò MR. 2013. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci, 14 (5), pp. 365-376. Read abstract | Read more

A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles. Hide abstract

Bi B, Xiao X, Zhang H, Gao J, Tao M, Niu H, Wang Y, Wang Q et al. 2012. A comparison of the clinical characteristics of women with recurrent major depression with and without suicidal symptomatology. Psychol Med, 42 (12), pp. 2591-2598. Read abstract | Read more

The relationship between recurrent major depression (MD) in women and suicidality is complex. We investigated the extent to which patients who suffered with various forms of suicidal symptomatology can be distinguished from those subjects without such symptoms. Hide abstract

Flint J, Eskin E. 2012. Genome-wide association studies in mice. Nat Rev Genet, 13 (11), pp. 807-817. Read abstract | Read more

Genome-wide association studies (GWASs) have transformed the field of human genetics and have led to the discovery of hundreds of genes that are implicated in human disease. The technological advances that drove this revolution are now poised to transform genetic studies in model organisms, including mice. However, the design of GWASs in mouse strains is fundamentally different from the design of human GWASs, creating new challenges and opportunities. This Review gives an overview of the novel study designs for mouse GWASs, which dramatically improve both the statistical power and resolution compared to classical gene-mapping approaches. Hide abstract

Goodson M, Rust MB, Witke W, Bannerman D, Mott R, Ponting CP, Flint J. 2012. Cofilin-1: a modulator of anxiety in mice. PLoS Genet, 8 (10), pp. e1002970. Read abstract | Read more

The genes involved in conferring susceptibility to anxiety remain obscure. We developed a new method to identify genes at quantitative trait loci (QTLs) in a population of heterogeneous stock mice descended from known progenitor strains. QTLs were partitioned into intervals that can be summarized by a single phylogenetic tree among progenitors and intervals tested for consistency with alleles influencing anxiety at each QTL. By searching for common Gene Ontology functions in candidate genes positioned within those intervals, we identified actin depolymerizing factors (ADFs), including cofilin-1 (Cfl1), as genes involved in regulating anxiety in mice. There was no enrichment for function in the totality of genes under each QTL, indicating the importance of phylogenetic filtering. We confirmed experimentally that forebrain-specific inactivation of Cfl1 decreased anxiety in knockout mice. Our results indicate that similarity of function of mammalian genes can be used to recognize key genetic regulators of anxiety and potentially of other emotional behaviours. Hide abstract

Gao J, Li Y, Cai Y, Chen J, Shen Y, Ni S, Wei Y, Qiu Y et al. 2012. Perceived parenting and risk for major depression in Chinese women. Psychol Med, 42 (5), pp. 921-930. Read abstract | Read more

In Western countries, a history of major depression (MD) is associated with reports of received parenting that is low in warmth and caring and high in control and authoritarianism. Does a similar pattern exist in women in China? Hide abstract

Cong E, Li Y, Shao C, Chen J, Wu W, Shang X, Wang Z, Liu Y et al. 2012. Childhood sexual abuse and the risk for recurrent major depression in Chinese women. Psychol Med, 42 (2), pp. 409-417. Read abstract | Read more

Studies in Western countries have repeatedly shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in China? Hide abstract

Chen Y, Li H, Li Y, Xie D, Wang Z, Yang F, Shen Y, Ni S et al. 2012. Resemblance of symptoms for major depression assessed at interview versus from hospital record review. PLoS One, 7 (1), pp. e28734. Read abstract | Read more

Diagnostic information for psychiatric research often depends on both clinical interviews and medical records. Although discrepancies between these two sources are well known, there have been few studies into the degree and origins of inconsistencies. Hide abstract

Mathieson I, Flint J, Munafò MR. 2012. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia Molecular 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. © 2012 Macmillan Publishers Limited All rights reserved. Hide abstract

Sun N, Li Y, Cai Y, Chen J, Shen Y, Sun J, Zhang Z, Zhang J et al. 2012. A comparison of melancholic and nonmelancholic recurrent major depression in Han Chinese women. Depress Anxiety, 29 (1), pp. 4-9. Read abstract | Read more

Although the diagnosis of melancholia has had a long history, the validity of the current DSM-IV definition remains contentious. We report here the first detailed comparison of melancholic and nonmelancholic major depression (MD) in a Chinese population examining in particular whether these two forms of MD differ quantitatively or qualitatively. Hide abstract

Wang L, Qiao D, Li Y, Wang L, Ren J, He K, Sun J, Wang Z et al. 2012. Clinical predictors of familial depression in Han Chinese women. Depress Anxiety, 29 (1), pp. 10-15. Read abstract | Read more

A number of clinical features potentially reflect an individual's familial vulnerability to major depression (MD), including early age at onset, recurrence, impairment, episode duration, and the number and pattern of depressive symptoms. However, these results are drawn from studies that have exclusively examined individuals from a European ethnic background. We investigated which clinical features of depressive illness index familial vulnerability in Han Chinese females with MD. Hide abstract

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. J Affect Disord, 135 (1-3), pp. 89-94. Read abstract | Read more

Individuals with early-onset depression may be a clinically distinct group with particular symptom patterns, illness course, comorbidity and family history. This question has not been previously investigated in a Han Chinese population. Hide abstract

Xia J, He Q, Li Y, Xie D, Zhu S, Chen J, Shen Y, Zhang N et al. 2011. The relationship between neuroticism, major depressive disorder and comorbid disorders in Chinese women. J Affect Disord, 135 (1-3), pp. 100-105. Read abstract | Read more

The personality trait of neuroticism is a risk factor for major depressive disorder (MDD), but this relationship has not been demonstrated in clinical samples from Asia. Hide abstract

Tao M, Li Y, Xie D, Wang Z, Qiu J, Wu W, Sun J, Wang Z et al. 2011. Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women. J Affect Disord, 135 (1-3), pp. 95-99. Read abstract | Read more

In European and US studies, patients with major depressive disorder (MDD) report more stressful life events (SLEs) than controls, but this relationship has rarely been studied in Chinese populations. Hide abstract

Sang W, Li Y, Su L, Yang F, Wu W, Shang X, Zhang G, Shen J et al. 2011. A comparison of the clinical characteristics of Chinese patients with recurrent major depressive disorder with and without dysthymia. J Affect Disord, 135 (1-3), pp. 106-110. Read abstract | Read more

The relationship between major depressive disorder (MDD) and dysthymia, a form of chronic depression, is complex. The two conditions are highly comorbid and it is unclear whether they are two separate disease entities. We investigated the extent to which patients with dysthymia superimposed on major depression can be distinguished from those with recurrent MDD. Hide abstract

Li Y, Shi S, Yang F, Gao J, Li Y, Tao M, Wang G, Zhang K et al. 2012. Patterns of co-morbidity with anxiety disorders in Chinese women with recurrent major depression. Psychol Med, 42 (6), pp. 1239-1248. Read abstract | Read more

Studies conducted in Europe and the USA have shown that co-morbidity between major depressive disorder (MDD) and anxiety disorders is associated with various MDD-related features, including clinical symptoms, degree of familial aggregation and socio-economic status. However, few studies have investigated whether these patterns of association vary across different co-morbid anxiety disorders. Here, using a large cohort of Chinese women with recurrent MDD, we examine the prevalence and associated clinical features of co-morbid anxiety disorders. Hide abstract

Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, Heger A, Agam A et al. 2011. Mouse genomic variation and its effect on phenotypes and gene regulation. Nature, 477 (7364), pp. 289-294. Read abstract | Read more

We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism. Hide abstract

Yalcin B, Wong K, Agam A, Goodson M, Keane TM, Gan X, Nellåker C, Goodstadt L et al. 2011. Sequence-based characterization of structural variation in the mouse genome. Nature, 477 (7364), pp. 326-329. Read abstract | Read more

Structural variation is widespread in mammalian genomes and is an important cause of disease, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1 kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions. Hide abstract

Ahlqvist E, Ekman D, Lindvall T, Popovic M, Förster 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. Hum Mol Genet, 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(2) 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(q) mice were then selected to set up an F(3) 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. 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

Chen J, Cai Y, Cong E, Liu Y, Gao J, Li Y, Tao M, Zhang K et al. 2014. Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women PLOS ONE, 9 (1), pp. 1-9. | Read more

Sun N, Li Y, Cai Y, Chen J, Shen Y, Sun J, Zhang Z, Zhang J et al. 2011. A comparison of melancholic and nonmelancholic recurrent major depression in Han Chinese women Depression and Anxiety, 4 (2),

Wang L, Qiao D, Li Y, Wang L, Ren J, He K, Sun J, Wang Z et al. 2011. Clinical predictors of familial depression in Han Chinese women Depression and Anxiety, 4 (2),

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. J Affect Disord, 136 (3), pp. 983-987. Read abstract | Read more

Post partum depression (PPD) is relatively common in China but its clinical characteristics and risk factors have not been studied. We set out to investigate whether known risk factors for PPD could be found in Chinese women. Hide abstract

Sang W, Li Y, Su L, Yang F, Wu W, Shang X, Zhang G, Shen J et al. 2011. A comparison of the clinical characteristics of Chinese patients with recurrent major depressive disorder with and without dysthymia Journal of Affective Disorders,

Tao M, Li Y, Xie D, Wang Z, Qiu J, Wu W, Sun J, Wang Z et al. 2011. Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women Journal of Affective Disorders,

Xia J, He Q, Li Y, Xie D, Zhu S, Chen J, Shen Y, Zhang N et al. 2011. The relationship between neuroticism, major depressive disorder and comorbid disorders in Chinese women Journal of Affective Disorders,

Gan Z, Li Y, Xie D, Shao C, Yang F, Shen Y, Zhang N, Zhang G et al. 2012. The impact of educational status on the clinical features of major depressive disorder among Chinese women. J Affect Disord, 136 (3), pp. 988-992. Read abstract | Read more

Years of education are inversely related to the prevalence of major depressive disorder (MDD), but the relationship between the clinical features of MDD and educational status is poorly understood. We investigated this in 1970 Chinese women with recurrent MDD identified in a clinical setting. Hide abstract

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, Cañete T, Blázquez G, López-Aumatell R, Martínez-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 abstract | Read more

Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. Hide abstract

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

We sought to ascertain the strength of evidence for association between the 5-HTTLPR polymorphism and unipolar depression. 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. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet, 11 (6), pp. 446-450. Read abstract | Read more

Although recent genome-wide studies have provided valuable insights into the genetic basis of human disease, they have explained relatively little of the heritability of most complex traits, and the variants identified through these studies have small effect sizes. This has led to the important and hotly debated issue of where the 'missing heritability' of complex diseases might be found. Here, seven leading geneticists offer their opinion about where this heritability is likely to lie, what this could tell us about the underlying genetic architecture of common diseases and how this could inform research strategies for uncovering genetic risk factors. Hide abstract

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. Am J Hum Genet, 86 (5), pp. 819-822. | Read more

Keays DA, Cleak J, Huang GJ, 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. Dev Neurosci, 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. 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

Munafò MR, Durrant C, Lewis G, Flint J. 2009. Gene X environment interactions at the serotonin transporter locus. Biol Psychiatry, 65 (3), pp. 211-219. Read abstract | Read more

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 x E) are not so well established. 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

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