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 University of Oxford United Kingdom
Nicholas Rawlins Experimental Psychology United Kingdom
David Bannerman Experimental Psychology United Kingdom
Prof Paul Klenerman Experimental Medicine Division University of Oxford United Kingdom
Christophe Benoist Joslin Institute, Harvard United States

Flint J, Cuijpers P, Horder J, Koole SL, Munafò MR. 2014. Is there an excess of significant findings in published studies of psychotherapy for depression? Psychol Med, 45 (2), pp. 1-8. Read abstract | Read more

BACKGROUND: Many studies have examined the efficacy of psychotherapy for major depressive disorder (MDD) but publication bias against null results may exist in this literature. However, to date, the presence of an excess of significant findings in this literature has not been explicitly tested. METHOD: We used a database of 1344 articles on the psychological treatment of depression, identified through systematic search in PubMed, PsycINFO, EMBASE and the Cochrane database of randomized trials. From these we identified 149 studies eligible for inclusion that provided 212 comparisons. We tested for an excess of significant findings using the method developed by Ioannidis and Trikalinos (2007), and compared the distribution of p values in this literature with the distribution in the antidepressant literature, where publication bias is known to be operating. RESULTS: The average statistical power to detect the effect size indicated by the meta-analysis was 49%. A total of 123 comparisons (58%) reported a statistically significant difference between treatment and control groups, but on the basis of the average power observed, we would only have expected 104 (i.e. 49%) to do so. There was therefore evidence of an excess of significance in this literature (p = 0.010). Similar results were obtained when these analyses were restricted to studies including a cognitive behavioural therapy (CBT) arm. Finally, the distribution of p values for psychotherapy studies resembled that for published antidepressant studies, where publication bias against null results has already been established. CONCLUSIONS: The small average size of individual psychotherapy studies is only sufficient to detect large effects. Our results indicate an excess of significant findings relative to what would be expected, given the average statistical power of studies of psychotherapy for major depression. Hide abstract

Flint J, Munafò M. 2014. Schizophrenia: genesis of a complex disease. Nature, 511 (7510), pp. 412-413. | Read more

Munafò MR, Flint J. 2014. Common or rare variants for complex traits? Biol Psychiatry, 75 (10), pp. 752-753. | Read more

Li Y, Aggen S, Shi S, Gao J, Li Y, Tao M, Zhang K, Wang X et al. 2014. Subtypes of major depression: latent class analysis in depressed Han Chinese women. Psychol Med, 44 (15), pp. 3275-3288. Read abstract | Read more

BACKGROUND: Despite substantial research, uncertainty remains about the clinical and etiological heterogeneity of major depression (MD). Can meaningful and valid subtypes be identified and would they be stable cross-culturally? METHOD: Symptoms at their 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. Latent class analysis (LCA) was performed in Mplus. RESULTS; Using the nine DSM-IV MD symptomatic A criteria, the 14 disaggregated DSM-IV criteria and all independently assessed depressive symptoms (n = 27), the best LCA model identified respectively three, four and six classes. A severe and non-suicidal class was seen in all solutions, as was a mild/moderate subtype. An atypical class emerged once bidirectional neurovegetative symptoms were included. The non-suicidal class demonstrated low levels of worthlessness/guilt and hopelessness. Patterns of co-morbidity, family history, personality, environmental precipitants, recurrence and body mass index (BMI) differed meaningfully across subtypes, with the atypical class standing out as particularly distinct. CONCLUSIONS: MD is a clinically complex syndrome with several detectable subtypes with distinct clinical and demographic correlates. Three subtypes were most consistently identified in our analyses: severe, atypical and non-suicidal. Severe and atypical MD have been identified in multiple prior studies in samples of European ethnicity. Our non-suicidal subtype, with low levels of guilt and hopelessness, may represent a pathoplastic variant reflecting Chinese cultural influences. Hide abstract

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

BACKGROUND: 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. METHODS: We re-examined the relationship between AAO and the clinical features of recurrent MD in Han Chinese women by analyzing the phase I (N=1848), phase II (N=4169) and total combined data (N=6017) from the CONVERGE project. Linear, logistic, multiple linear and multinomial logistic regression models were used to determine the association of AAO with continuous, binary and categorical variables. RESULTS: The effect size of the association between AAO and clinical features of MD was quite similar in the phase I and phase II samples. These results confirmed that MD patients with earlier AAO tended to suffer more severe, recurrent and chronic illness and cases of MD with earlier AAO showed increased neuroticism, greater family history and psychiatric comorbidity. In addition, we showed that earlier AAO of MD in Han Chinese women was associated with premenstrual symptoms, postnatal depression, a highly authoritarian or cold childhood parental rearing style and a reduced probability for having melancholia. LIMITATIONS: Data were collected retrospectively through interview and recall bias may have affected the results. CONCLUSIONS: MD with earlier AAO in Han Chinese women shows a distinct set of clinical features which are similar to those reported in Western populations. 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

BACKGROUND: 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. METHODS: We assessed 22 phobic fears in 6017 Han Chinese women with MD. We used exploratory factor analysis to examine the structure of these phobic fears. We examined the relationship between individual phobic fears and the severity of MD, neuroticism, comorbid panic disorder, generalized anxiety disorder and dysthymia using logistic regression models. RESULTS: The frequency of phobic fears ranged from 3.0% (eating in public) to 36.0% (snakes). Phobic fears were significantly associated with more severe MD, high neuroticism, and co-morbid panic disorder, generalized anxiety disorder and dysthymia. Our factor analysis suggested four underlying subgroups of phobic fears which differed in their clinical correlates, severity and patterns of comorbidity. LIMITATIONS: Data were collected retrospectively through interview and recall bias may have affected the results. CONCLUSIONS: Phobic fears are correlated with comorbid MD and more severe MD. These phobic fears clearly subdivide into four subgroups that differ meaningfully from each other. 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

BACKGROUND: 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? METHOD: Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. RESULTS: We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19-5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58-3.15), genital (OR 5.24, 95% CI 3.52-8.15) and intercourse (OR 10.65, 95% CI 5.56-23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11-2.27) and phobia (OR 1.41, 95%CI 1.09-1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20-1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02-2.02). Intercourse (OR 3.47, 95%CI 1.66-8.22), use of force and threats (OR 1.95, 95%CI 1.05-3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20-1.64) were significantly associated with recurrent MD. CONCLUSIONS: In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD. 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

BACKGROUND: 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. PRINCIPAL FINDINGS: We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25-0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77-0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86-0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders. CONCLUSIONS: In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype. Hide abstract

Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, Munafò MR. 2013. Empirical evidence for low reproducibility indicates low pre-study odds. Nat Rev Neurosci, 14 (12), pp. 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

BACKGROUND: 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. METHOD: The three key cognitive symptoms of worthlessness, hopelessness and helplessness were assessed during their lifetime worst episode in 1970 Han Chinese women with recurrent MD. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. RESULTS: Compared to patients who did not endorse the cognitive trio, those who did had a greater number of DSM-IV A criteria, more individual depressive symptoms, an earlier age at onset, a greater number of episodes, and were more likely to meet diagnostic criteria for melancholia, postnatal depression, dysthymia and anxiety disorders. Hopelessness was highly related to all the suicidal symptomatology, with ORs ranging from 5.92 to 6.51. Neuroticism, stressful life events (SLEs) and a protective parental rearing style were associated with these cognitive symptoms. CONCLUSIONS: During the worst episode of MD in Han Chinese women, the endorsement of the cognitive trio was associated with a worse course of depression and an increased risk of suicide. Individuals with high levels of neuroticism, many SLEs and high parental protectiveness were at increased risk for these cognitive depressive symptoms. As in Western populations, symptoms of the cognitive trio appear to play a central role in the psychopathology of MD in Chinese women. 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. 2014. The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women. Psychol Med, 44 (7), pp. 1391-1401. Read abstract | Read more

BACKGROUND: 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. RESULTS: The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety. CONCLUSIONS: MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome. 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

BACKGROUND: 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. METHOD: We examined the clinical features of the worst episode in 1970 Han Chinese women with recurrent DSM-IV MD between the ages of 30 and 60 years from across China. Student's t tests, and logistic and multiple logistic regression models were used to determine the association between suicidality and other clinical features of MD. RESULTS: Suicidal symptomatology is significantly associated with a more severe form of MD, as indexed by both the number of episodes and number of MD symptoms. Patients reporting suicidal thoughts, plans or attempts experienced a significantly greater number of stressful life events. The depressive symptom most strongly associated with lifetime suicide attempt was feelings of worthlessness (odds ratio 4.25, 95% confidence interval 2.9-6.3). Excessive guilt, diminished concentration and impaired decision-making were also significantly associated with a suicide attempt. CONCLUSIONS: This study contributes to the existing literature on risk factors for suicidal symptomatology in depressed women. Identifying specific depressive symptoms and co-morbid psychiatric disorders may help improve the clinical assessment of suicide risk in depressed patients. These findings could be helpful in identifying those who need more intense treatment strategies in order to prevent suicide. 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

BACKGROUND: 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? METHOD: Received parenting was assessed by a shortened version of the Parental Bonding Instrument (PBI) in two groups of Han Chinese women: 1970 clinically ascertained cases with recurrent MD and 2597 matched controls. MD was assessed at personal interview. RESULTS: Factor analysis of the PBI revealed three factors for both mothers and fathers: warmth, protectiveness, and authoritarianism. Lower warmth and protectiveness and higher authoritarianism from both mother and father were significantly associated with risk for recurrent MD. Parental warmth was positively correlated with parental protectiveness and negatively correlated with parental authoritarianism. When examined together, paternal warmth was more strongly associated with lowered risk for MD than maternal warmth. Furthermore, paternal protectiveness was negatively and maternal protectiveness positively associated with risk for MD. CONCLUSIONS: Although the structure of received parenting is very similar in China and Western countries, the association with MD is not. High parental protectiveness is generally pathogenic in Western countries but protective in China, especially when received from the father. Our results suggest that cultural factors impact on patterns of parenting and their association with MD. 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

BACKGROUND: 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? METHOD: Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression and regression coefficients by linear or Poisson regression. RESULTS: Any form of CSA was significantly associated with recurrent MD [OR 3.26, 95% confidence interval (CI) 1.95-5.45]. This association strengthened with increasing CSA severity: non-genital (OR 2.47, 95% CI 1.17-5.23), genital (OR 2.77, 95% CI 1.32-5.83) and intercourse (OR 13.35, 95% CI 1.83-97.42). The association between any form of CSA and MD remained significant after accounting for parental history of depression, childhood emotional neglect (CEN), childhood physical abuse (CPA) and parent-child relationship. Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes and an increased risk for generalized anxiety disorder (GAD; OR 1.92, 95% CI 1.39-2.66) and dysthymia (OR 2.16, 95% CI 1.52-3.09). CONCLUSIONS: In Chinese women CSA is strongly associated with MD and this association increases with greater severity of CSA. Depressed women with CSA have an earlier age of onset, longer depressive episodes and increased co-morbidity with GAD and dysthymia. Although reporting biases cannot be ruled out, our results are consistent with the hypothesis that, as in Western countries, CSA substantially increases the risk for MD 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

BACKGROUND: 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. PRINCIPAL FINDINGS: We compared data from structured interviews and medical records on 1,970 Han Chinese women with recurrent DSM-IV major depression (MD). Correlations were high for age at onset of MD (0.93) and number of episodes (0.70), intermediate for family history (+0.62) and duration of longest episode (+0.43) and variable but generally more modest for individual depressive symptoms (mean kappa = 0.32). Four factors were identified for twelve symptoms from medical records and the same four factors emerged from analysis of structured interviews. Factor congruencies were high but the correlation of factors between interviews and records were modest (i.e. +0.2 to +0.4). CONCLUSIONS: Structured interviews and medical records are highly concordant for age of onset, and the number and length of episodes, but agree more modestly for individual symptoms and symptom factors. The modesty of these correlations probably arises from multiple factors including i) inconsistency in the definition of the worst episode, ii) inaccuracies in self-report and iii) difficulties in coding medical records where symptoms were recorded solely for clinical purposes. Hide abstract

Mathieson I, Munafò MR, Flint J. 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

BACKGROUND: 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. METHODS: DSM-IV criteria for melancholia were applied to 1,970 Han Chinese women with recurrent MD recruited from 53 provincial mental health centers and psychiatric departments of general medical hospitals in 41 cities. Statistical analyses, utilizing Student's t-tests and Pearson's χ(2) , were calculated using SPSS 13.0. RESULTS: Melancholic patients with MD were distinguished from nonmelancholic by being older, having a later age at onset, more episodes of illness and meeting more A criteria. They also had higher levels of neuroticism and rates of lifetime generalized anxiety disorder, panic disorder, and social and agoraphobia. They had significantly lower rates of childhood sexual abuse but did not differ on other stressful life events or rates of MD in their families. DISCUSSION: Consistent with most prior findings in European and US populations, we find that melancholia is a more clinically severe syndrome than nonmelancholic depression with higher rates of comorbidity. The evidence that it is a more "biological" or qualitatively distinct syndrome, however, is mixed. 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

BACKGROUND: 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. METHODS: We used lifetime MD and associated clinical features assessed at personal interview in 1,970 Han Chinese women with DSM-IV MD between 30-60 years of age. Odds Ratios were calculated by logistic regression. RESULTS: Individuals with a high familial risk for MD are characterized by severe episodes of MD without known precipitants (such as stress life events) and are less likely to feel irritable/angry or anxious/nervous. CONCLUSIONS: The association between family history of MD and the lack of a precipitating stressor, traditionally a characteristic of endogenous or biological depression, may reflect the association seen in other samples between recurrent MD and a positive family history. The symptomatic associations we have seen may reflect a familial predisposition to other dimensions of psychopathology, such as externalizing disorders or anxiety states. 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

BACKGROUND: 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. METHODS: We examined the clinical features of 1970 Han Chinese women with DSM-IV major depressive disorder (MDD) between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models was used to determine the association between age at onset (AAO) with continuous, binary and discrete characteristic clinical features of MDD. RESULTS: Earlier AAO was associated with more suicidal ideation and attempts and higher neuroticism, but fewer sleep, appetite and weight changes. Patients with an earlier AAO were more likely to suffer a chronic course (longer illness duration, more MDD episodes and longer index episode), increased rates of MDD in their parents and a lower likelihood of marriage. They tend to have higher comorbidity with anxiety disorders (general anxiety disorder, social phobia and agoraphobia) and dysthymia. CONCLUSIONS: Early AAO in MDD may be an index of a more severe, highly comorbid and familial disorder. Our findings indicate that the features of MDD in China are similar to those reported elsewhere in the world. 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

OBJECTIVE: 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. METHODS: We examined a large-scale clinical study of Chinese Han women with recurrent major depression and community-acquired controls. RESULTS: Elevated levels of neuroticism increased the risk for lifetime MDD (with an odds ratio of 1.37 per SD), contributed to the comorbidity of MDD with anxiety disorders, and predicted the onset and severity of MDD. Our findings largely replicate those obtained in clinical populations in Europe and US but differ in two ways: we did not find a relationship between melancholia and neuroticism; we found lower mean scores for neuroticism (3.6 in our community control sample). LIMITATIONS: Our findings do not apply to MDD in community-acquired samples and may be limited to Han Chinese women. It is not possible to determine whether the association between neuroticism and MDD reflects a causal relationship. CONCLUSIONS: Neuroticism acts as a risk factor for MDD in Chinese women, as it does in the West and may particularly predispose to comorbidity with anxiety disorders. Cultural factors may have an important effect on its measurement. 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

BACKGROUND: 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. METHODS: Sixteen lifetime SLEs were assessed at interview in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MDD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. RESULTS: 60% of controls and 72% of cases reported at least one lifetime SLE. Fourteen of the sixteen SLEs occurred significantly more frequently in those with MDD (median odds ratio of 1.6). The three SLEs most strongly associated with risk for MDD (OR>3.0) preceded the onset of MDD the majority of the time: rape (82%), physical abuse (100%) and serious neglect (99%). LIMITATIONS: Our results may apply to females only. SLEs were rated retrospectively and are subject to biases in recollection. We did not assess contextual information for each life event. CONCLUSIONS: More severe SLEs are more strongly associated with MDD. These results support the involvement of psychosocial adversity in the etiology of MDD in China. 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

BACKGROUND: 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. METHODS: We examined the clinical features in 1970 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and dysthymia and between dysthymia and disorders comorbid with major depression. RESULTS: The 354 cases with dysthymia had more severe MDD than those without, with more episodes of MDD and greater co-morbidity for anxiety disorders. Patients with dysthymia had higher neuroticism scores and were more likely to have a family history of MDD. They were also more likely to have suffered serious life events. LIMITATIONS: Results were obtained in a clinically ascertained sample of Chinese women and may not generalize to community-acquired samples or to other populations. It is not possible to determine whether the associations represent causal relationships. CONCLUSIONS: The additional diagnosis of dysthymia in Chinese women with recurrent MDD defines a meaningful and potentially important subtype. We conclude that in some circumstances it is possible to distinguish double depression from 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

BACKGROUND: 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. METHOD: A total of 1970 female Chinese MDD patients with or without seven co-morbid anxiety disorders [including generalized anxiety disorder (GAD), panic disorder, and five phobia subtypes] were ascertained in the CONVERGE study. Generalized linear models were used to model association between co-morbid anxiety disorders and various MDD features. RESULTS: The lifetime prevalence rate for any type of co-morbid anxiety disorder is 60.2%. Panic and social phobia significantly predict an increased family history of MDD. GAD and animal phobia predict an earlier onset of MDD and a higher number of MDD episodes, respectively. Panic and GAD predict a higher number of DSM-IV diagnostic criteria. GAD and blood-injury phobia are both significantly associated with suicidal attempt with opposite effects. All seven co-morbid anxiety disorders predict higher neuroticism. CONCLUSIONS: Patterns of co-morbidity between MDD and anxiety are consistent with findings from the US and European studies; the seven co-morbid anxiety disorders are heterogeneous when tested for association with various MDD features. 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

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

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

BACKGROUND: 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. METHODS: A case control design was used to determine the impact of known risk factors for PPD in a cohort of 1970 Chinese women with recurrent DSM-IV major depressive disorder (MDD). In a within-case design we examined the risk factors for PPD in patients with recurrent MDD. We compared the clinical features of MDD in cases with PPD to those without MDD. Odds ratios were calculated using logistic and ordinal regression. RESULTS: Lower occupational and educational statuses increased the risk of PPD, as did a history of pre-menstrual symptoms, stressful life events and elevated levels of the personality trait of neuroticism. Patients with PPD and MDD were more likely to experience a comorbid anxiety disorder, had a younger age of onset of MDD, have higher levels of neuroticism and dysthymia. LIMITATIONS: Results obtained in this clinical sample may not be applicable to PPD within the community. Data were obtained retrospectively and we do not know whether the correlations we observe have the same causes as those operating in other populations. CONCLUSIONS: Our results are consistent with the hypothesis that the despite cultural differences between Chinese and Western women, the phenomenology and risk factors for PPD are very similar. 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

BACKGROUND: 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. METHODS: Clinical and demographic features were obtained from 1970 Han Chinese women with DSM-IV major depression between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models were used to determine the association between educational level and clinical features of MDD. RESULTS: Subjects with more years of education are more likely to have MDD, with an odds ratio of 1.14 for those with more than ten years. Low educational status is not associated with an increase in the number of episodes, nor with increased rates of co-morbidity with anxiety disorders. Education impacts differentially on the symptoms of depression: lower educational attainment is associated with more biological symptoms and increased suicidal ideation and plans to commit suicide. LIMITATIONS: Findings may not generalize to males or to other patient populations. Since the threshold for treatment seeking differs as a function of education there may an ascertainment bias in the sample. CONCLUSIONS: The relationship between symptoms of MDD and educational status in Chinese women is unexpectedly complex. Our findings are inconsistent with the simple hypothesis from European and US reports that low levels of educational attainment increase the risk and severity of MDD. 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,

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

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. 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

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 x E) are not so well established. METHODS: We carried out a systematic review and meta-analysis of the serotonin transporter (5-HTTLPR) polymorphic region x stressful life event (SLE) literature and investigated to what extent the main effects reported in this literature are consistent with a number of G x 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 x SLE interactions in logistic regression models are compatible with chance findings. 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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