Flint group publications
2013. Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic model. PLoS Genet, 9 (9), 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
2013. The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women. Psychol Med, 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
2013. Confidence and precision increase with high statistical power Nature Reviews Neuroscience, 14 (8), | Read more
2013. Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes CELL, 154 (2), Read abstract | Read more
Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PaperClip © 2013 The Authors. Hide abstract
2013. Dissecting Quantitative Traits in Mice. Annu Rev Genomics Hum Genet, 14 (1), Read abstract | Read more
Progress in complex trait mapping in mice has been accelerated by the development of new populations suited to high-resolution mapping and by statistical methodologies that control for population structure. When combined with newly acquired catalogs of sequence variation in inbred strains, the genetic architecture of these new populations makes it possible to dissect complex traits down to the level of single variants. These analyses have shown not only that complex traits are caused by multiple contributing loci but also that each locus is likely due to the combined effects of multiple causal DNA variants. In combination with new rapid methods for producing transgenic mice that make it efficient to test candidate genes and variants, these advances significantly enhance the mouse genetics toolbox for dissecting quantitative traits. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is August 31, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. Hide abstract
2013. Confidence and precision increase with high statistical power NATURE REVIEWS NEUROSCIENCE, 14 (8), | Read more
2013. Genetics. Herit-ability. Science, 340 (6139), Read abstract | Read more
A genome-wide association study reveals possible variants that influence the complex behavior of educational attainment. Hide abstract
2013. [Genome sequencing and genetic mapping to dissect the genetic basis of complex traits]. Med Sci (Paris), 29 (6-7), | Read more
2013. Causes and Consequences of Chromatin Variation between Inbred Mice. PLoS Genet, 9 (6), 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
2013. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet, 45 (7), 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
2013. Power failure: Why small sample size undermines the reliability of neuroscience Nature Reviews Neuroscience, 14 (5), 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
2013. GWAS. Curr Biol, 23 (7), | Read more
2013. Power failure: why small sample size undermines the reliability of neuroscience NATURE REVIEWS NEUROSCIENCE, 14 (5), | Read more
2013. Mutation of the Diamond-Blackfan Anemia Gene Rps7 in Mouse Results in Morphological and Neuroanatomical Phenotypes PLOS GENETICS, 9 (1), Read abstract | Read more
The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7 and Rps7) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes. Hide abstract
2013. Candidate and non-candidate genes in behavior genetics Current Opinion in Neurobiology, 23 (1), Read abstract | Read more
In this review we discuss recent developments in psychiatric genetics: on the one hand, studies using whole genome approaches (genome-wide association studies (GWAS) and exome sequencing) are coming close to finding genes and molecular variants that contribute to disease susceptibility; on the other candidate genes, such as the serotonin transporter, continue to dominate in genetic studies of brain imaging phenotypes and in protracted searches for gene by environment interactions. These two areas intersect, in that new information about genetic effects from whole genome approaches, should (but does not always) inform the single locus analyses. © 2012 Elsevier Ltd. Hide abstract
2012. A comparison of the clinical characteristics of women with recurrent major depression with and without suicidal symptomatology PSYCHOLOGICAL MEDICINE, 42 (12), | Read more
2012. Genome-wide association studies in mice. Nat Rev Genet, 13 (11), 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
2012. Next-generation sequencing of experimental mouse strains MAMMALIAN GENOME, 23 (9-10), | Read more
2012. Cofilin-1: a modulator of anxiety in mice. PLoS Genet, 8 (10), 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
2012. Association studies in outbred mice in a new era of full-genome sequencing MAMMALIAN GENOME, 23 (9-10), | Read more
2012. Direct blood PCR in combination with nucleic acid lateral flow immunoassay for detection of Plasmodium species in settings where malaria is endemic. J Clin Microbiol, 50 (11), Read abstract | Read more
Declining malaria transmission and known difficulties with current diagnostic tools for malaria, such as microscopy and rapid diagnostic tests (RDTs) in particular at low parasite densities, still warrant the search for sensitive diagnostic tests. Molecular tests need substantial simplification before implementation in clinical settings in countries where malaria is endemic. Direct blood PCR (db-PCR), circumventing DNA extraction, to detect Plasmodium was developed and adapted to be visualized by nucleic acid lateral flow immunoassay (NALFIA). The assay was evaluated in the laboratory against samples from confirmed Sudanese patients (n = 51), returning travelers (n = 214), samples from the Dutch Blood Bank (n = 100), and in the field in Burkina Faso (n = 283) and Thailand (n = 381) on suspected malaria cases and compared to RDT and microscopy. The sensitivity and specificity of db-PCR-NALFIA compared to the initial diagnosis in the laboratory were 94.4% (95% confidence interval [CI] = 0.909 to 0.969) and 97.4% (95% CI = 0.909 to 0.969), respectively. In Burkina Faso, the sensitivity was 94.8% (95% CI = 0.88.7 to 97.9%), and the specificity was 82.4% (95% CI = 75.4 to 87.7%) compared to microscopy and 93.3% (95% CI = 87.4 to 96.7%) and 91.4% (95% CI = 85.2 to 95.3%) compared to RDT. In Thailand, the sensitivity and specificity were 93.4% (CI = 86.4 to 97.1%) and 90.9 (95% CI = 86.7 to 93.9%), respectively, compared to microscopy and 95.6% (95% CI = 88.5 to 98.6%) and 87.1% (95% CI = 82.5 to 90.6) compared to RDT. db-PCR-NALFIA is highly sensitive and specific for easy and rapid detection of Plasmodium parasites and can be easily used in countries where malaria is endemic. The inability of the device to discriminate Plasmodium species requires further investigation. Hide abstract
2012. Development, validation and evaluation of a rapid PCR-nucleic acid lateral flow immuno-assay for the detection of Plasmodium and the differentiation between Plasmodium falciparum and Plasmodium vivax. Malar J, 11 (1), Read abstract | Read more
Molecular tools are very sensitive and specific and could be an alternative for the diagnosis of malaria. The complexity and need for expensive equipment may hamper implementation and, therefore, simplifications to current protocols are warranted. Hide abstract
2013. Candidate and non-candidate genes in behavior genetics. Curr Opin Neurobiol, 23 (1), Read abstract | Read more
In this review we discuss recent developments in psychiatric genetics: on the one hand, studies using whole genome approaches (genome-wide association studies (GWAS) and exome sequencing) are coming close to finding genes and molecular variants that contribute to disease susceptibility; on the other candidate genes, such as the serotonin transporter, continue to dominate in genetic studies of brain imaging phenotypes and in protracted searches for gene by environment interactions. These two areas intersect, in that new information about genetic effects from whole genome approaches, should (but does not always) inform the single locus analyses. Hide abstract
2012. Anxious, hypoactive phenotype combined with motor deficits in Gtf2ird1 null mouse model relevant to Williams syndrome. Behav Brain Res, 233 (2), Read abstract | Read more
Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by a hemizygous deletion of around 28 genes on the long arm of chromosome 7 (7q11.23), characterized by a unique spectrum of behavioral impairments, including mental retardation, deficits in visuospatial constructive cognition, hypersociability, anxiety and simple phobias. Physical characteristics include dysmorphic faces, short stature, oculomotor deficits, gross and fine coordination impairments, diminished control of balance and mild extrapyramidal signs as well as gait abnormalities resembling gait hypokinesia. Genes near the distal deletion breakpoint appear to contribute most to the WBS cognitive and behavioral profile and include the GTF family of transcription factors: GTF2I, GTF2IRD1, GTF2IRD2. We have previously shown that heterozygous deletions of GTF2IRD1 in humans and homozygous deletion in mice contributes to craniofacial abnormalities. Here we show an important role of this gene in motor coordination and anxiety ascertained from extensive behavioral mouse phenotyping. Gtf2ird1 null mice showed lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress. Gtf2ird1 heterozygous mice displayed lower body weight and decreased circadian activity, but only minor motor coordination and anxiety-related behavioral dysfunctions. Our study strongly supports a role for GTF2IRD1 in the motoric and anxiety-related abnormalities seen in Williams-Beuren syndrome, and suggests basal ganglia and potentially cerebellar abnormalities in Gtf2ird1 mice. Hide abstract
2012. Perceived parenting and risk for major depression in Chinese women PSYCHOLOGICAL MEDICINE, 42 (5), | Read more
2012. Neurogenomic Evidence for a Shared Mechanism of the Antidepressant Effects of Exercise and Chronic Fluoxetine in Mice PLOS ONE, 7 (4), | Read more
2012. The fine-scale architecture of structural variants in 17 mouse genomes. Genome Biol, 13 (3), Read abstract | Read more
Accurate catalogs of structural variants (SVs) in mammalian genomes are necessary to elucidate the potential mechanisms that drive SV formation and to assess their functional impact. Next generation sequencing methods for SV detection are an advance on array-based methods, but are almost exclusively limited to four basic types: deletions, insertions, inversions and copy number gains. Hide abstract
2012. Childhood sexual abuse and the risk for recurrent major depression in Chinese women PSYCHOLOGICAL MEDICINE, 42 (2), | Read more
2012. Intragenic enhancers act as alternative promoters. Mol Cell, 45 (4), Read abstract | Read more
A substantial amount of organismal complexity is thought to be encoded by enhancers which specify the location, timing, and levels of gene expression. In mammals there are more enhancers than promoters which are distributed both between and within genes. Here we show that activated, intragenic enhancers frequently act as alternative tissue-specific promoters producing a class of abundant, spliced, multiexonic poly(A)(+) RNAs (meRNAs) which reflect the host gene's structure. meRNAs make a substantial and unanticipated contribution to the complexity of the transcriptome, appearing as alternative isoforms of the host gene. The low protein-coding potential of meRNAs suggests that many meRNAs may be byproducts of enhancer activation or underlie as-yet-unidentified RNA-encoded functions. Distinguishing between meRNAs and mRNAs will transform our interpretation of dynamic changes in transcription both at the level of individual genes and of the genome as a whole. Hide abstract
2012. Resemblance of Symptoms for Major Depression Assessed at Interview versus from Hospital Record Review PLOS ONE, 7 (1), | Read more
2012. High levels of RNA-editing site conservation amongst 15 laboratory mouse strains. Genome Biol, 13 (4), Read abstract | Read more
Adenosine-to-inosine (A-to-I) editing is a site-selective post-transcriptional alteration of double-stranded RNA by ADAR deaminases that is crucial for homeostasis and development. Recently the Mouse Genomes Project generated genome sequences for 17 laboratory mouse strains and rich catalogues of variants. We also generated RNA-seq data from whole brain RNA from 15 of the sequenced strains. Hide abstract
2012. Intragenic Enhancers Act as Alternative Promoters Molecular Cell, 45 (4),
2012. CLINICAL PREDICTORS OF FAMILIAL DEPRESSION IN HAN CHINESE WOMEN DEPRESSION AND ANXIETY, 29 (1), | Read more
2012. Deficiency for the ubiquitin ligase ube3b in a blepharophimosis-ptosis- intellectual-disability syndrome American Journal of Human Genetics, 91 (6), Read abstract | Read more
Ubiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis- ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals. © 2012 The American Society of Human Genetics. Hide abstract
2012. Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome AMERICAN JOURNAL OF HUMAN GENETICS, 91 (6), | Read more
2012. The genomic landscape shaped by selection on transposable elements across 18 mouse strains. Genome Biol, 13 (6), Read abstract | Read more
Transposable element (TE)-derived sequence dominates the landscape of mammalian genomes and can modulate gene function by dysregulating transcription and translation. Our current knowledge of TEs in laboratory mouse strains is limited primarily to those present in the C57BL/6J reference genome, with most mouse TEs being drawn from three distinct classes, namely short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs) and the endogenous retrovirus (ERV) superfamily. Despite their high prevalence, the different genomic and gene properties controlling whether TEs are preferentially purged from, or are retained by, genetic drift or positive selection in mammalian genomes remain poorly defined. Hide abstract
2012. The best of times, the worst of times for psychiatric disease NATURE NEUROSCIENCE, 15 (6), Read abstract | Read more
As long-awaited advances in psychiatric genetics begin to materialize in force, promising to steer us safely to the best of times in psychiatric disease research, many pharmaceutical companies pull away from the challenge of drug development, threatening to bring us to the worst of times for the field. There is a real danger of missed opportunities and a sense of urgency for defining a clear path forward. © 2012 Nature America, Inc. All rights reserved. Hide abstract
2012. Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes EUROPEAN JOURNAL OF HUMAN GENETICS, 20 (10), | Read more
2012. A COMPARISON OF MELANCHOLIC AND NONMELANCHOLIC RECURRENT MAJOR DEPRESSION IN HAN CHINESE WOMEN DEPRESSION AND ANXIETY, 29 (1), | Read more
2012. Intragenic Enhancers Act as Alternative Promoters Molecular Cell, 45 (4), Read abstract | Read more
A substantial amount of organismal complexity is thought to be encoded by enhancers which specify the location, timing, and levels of gene expression. In mammals there are more enhancers than promoters which are distributed both between and within genes. Here we show that activated, intragenic enhancers frequently act as alternative tissue-specific promoters producing a class of abundant, spliced, multiexonic poly(A) RNAs (meRNAs) which reflect the host gene's structure. meRNAs make a substantial and unanticipated contribution to the complexity of the transcriptome, appearing as alternative isoforms of the host gene. The low protein-coding potential of meRNAs suggests that many meRNAs may be byproducts of enhancer activation or underlie as-yet-unidentified RNA-encoded functions. Distinguishing between meRNAs and mRNAs will transform our interpretation of dynamic changes in transcription both at the level of individual genes and of the genome as a whole. © 2012 Elsevier Inc.. Hide abstract
2012. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia Molecular Psychiatry, 17 (6), 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
2011. Age at onset of major depressive disorder in Han Chinese women: Relationship with clinical features and family history JOURNAL OF AFFECTIVE DISORDERS, 135 (1-3), | Read more
2011. A comparison of the clinical characteristics of Chinese patients with recurrent major depressive disorder with and without dysthymia JOURNAL OF AFFECTIVE DISORDERS, 135 (1-3), | Read more
2011. The relationship between neuroticism, major depressive disorder and comorbid disorders in Chinese women JOURNAL OF AFFECTIVE DISORDERS, 135 (1-3), | Read more
2011. Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women JOURNAL OF AFFECTIVE DISORDERS, 135 (1-3), | Read more
2012. Patterns of co-morbidity with anxiety disorders in Chinese women with recurrent major depression. Psychol Med, 42 (6), 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
2011. Prioritization and Association Analysis of Murine-Derived Candidate Genes in Anxiety-Spectrum Disorders BIOLOGICAL PSYCHIATRY, 70 (9), | Read more
2012. Epilogue: Lessons from the CONVERGE study of major depressive disorder in China. J Affect Disord, 140 (1), Read abstract | Read more
This review summarizes the first clinical reports from the CONVERGE consortium: China, Oxford and VCU Experimental Research on Genetic Epidemiology. CONVERGE sets out to investigate the nature and mode of action of the genetic and environmental risk factors for major depressive disorder (MDD). CONVERGE aims to collect 6000 cases of recurrent MDD and 6000 controls. The consortium includes hospitals in 30 cities, all with populations exceeding 5million, and has collected over 2000 cases and controls. High quality phenotype data on MDD collected in China is now available to determine the source and nature of this highly heterogeneous condition. Analyses reported in a series of papers indicate that the clinical features and risk factors of MDD are sufficiently similar to those in the West that we can confidently predict that the results of subsequent analyses will be widely applicable. Hide abstract
2011. Mouse genomic variation and its effect on phenotypes and gene regulation. Nature, 477 (7364), 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
2011. Sequence-based characterization of structural variation in the mouse genome. Nature, 477 (7364), 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
2011. Genome-Wide and Species-Wide Dissection of the Genetics of Arthritis Severity in Heterogeneous Stock Mice ARTHRITIS AND RHEUMATISM, 63 (9), | Read more
2011. Dissecting the genetic architecture of human personality TRENDS IN COGNITIVE SCIENCES, 15 (9), Read abstract | Read more
The first candidate gene studies of human personality promised much but, in the fifteen years since their publication, have delivered little in the way of clear evidence for the contribution of specific genetic variants to observed variation in personality traits. This is most likely due to the very small effects conferred by individual loci. The advent of genome-wide association studies has brought growing awareness that high levels of statistical stringency, very large sample sizes, and independent replication will be minimum requirements for future genetic studies of personality. At the same time, evidence from other fields indicates that the genetic architecture of personality is likely to consist of the combined effect of many hundreds, if not thousands, of small effect loci. © 2011 Elsevier Ltd. Hide abstract
2011. Cytoarchitectural disruption of the superior colliculus and an enlarged acoustic startle response in the Tuba1a mutant mouse. Neuroscience, 195 Read abstract | Read more
The Jenna mutant mouse harbours an S140G mutation in Tuba1a that impairs tubulin heterodimer formation resulting in defective neuronal migration during development. The consequence of decreased neuronal motility is a fractured pyramidal cell layer in the hippocampus and wave-like perturbations in the cerebral cortex. Here, we extend our characterisation of this mouse investigating the laminar architecture of the superior colliculus (SC). Our results reveal that the structure of the SC in mutant animals is intact; however, it is significantly thinner with an apparent fusion of the intermediate grey and white layers. Birthdate labelling at E12.5 and E13.5 showed that the S140G mutation impairs the radial migration of neurons in the SC. A quantitative assessment of neuronal number in adulthood reveals a massive reduction in postmitotic neurons in mutant animals, which we attribute to increased apoptotic cell death. Consistent with the role of the SC in modulating sensorimotor gating, and the circuitry that modulates this behaviour, we find that Jenna mutants exhibit an exaggerated acoustic startle response. Our results highlight the importance of Tuba1a for correct neuronal migration and implicate postnatal apoptotic cell death in the pathophysiological mechanisms underlying the tubulinopathies. Hide abstract
2011. High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice HUMAN MOLECULAR GENETICS, 20 (15), Read abstract | Read more
Resolving the genetic basis of complex diseases like rheumatoid arthritis will require knowledge of the corresponding diseases in experimental animals to enable translational functional studies. Mapping of quantitative trait loci in mouse models of arthritis, such as collagen-induced arthritis (CIA), using F crosses has been successful, but can resolve loci only to large chromosomal regions. Using an inbred-outbred cross design, we identified and fine-mapped CIA loci on a genome-wide scale. Heterogeneous stock mice were first intercrossed with an inbred strain, B10.Q, to introduce an arthritis permitting MHCII haplotype. Homozygous H2 mice were then selected to set up an F generation with fixed major histocompatibility complex that was used for arthritis experiments. We identified 26 loci, 18 of which are novel, controlling arthritis traits such as incidence of disease, severity and time of onset and fine-mapped a number of previously mapped loci. © The Author 2011. Published by Oxford University Press. All rights reserved. Hide abstract
2011. Heritability and its Discontents EUROPEAN JOURNAL OF PERSONALITY, 25 (4),
2012. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry, 17 (6), 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
2011. Effects of environmental and physiological covariates on sex differences in unconditioned and conditioned anxiety and fear in a large sample of genetically heterogeneous (N/Nih-HS) rats. Behav Brain Funct, 7 (1), Read abstract | Read more
Physiological and environmental variables, or covariates, can account for an important portion of the variability observed in behavioural/physiological results from different laboratories even when using the same type of animals and phenotyping procedures. We present the results of a behavioural study with a sample of 1456 genetically heterogeneous N/Nih-HS rats, including males and females, which are part of a larger genome-wide fine-mapping QTL (Quantitative Trait Loci) study. N/Nih-HS rats have been derived from 8 inbred strains and provide very small distance between genetic recombinations, which makes them a unique tool for fine-mapping QTL studies. The behavioural test battery comprised the elevated zero-maze test for anxiety, novel-cage (open-field like) activity, two-way active avoidance acquisition (related to conditioned anxiety) and context-conditioned freezing (i.e. classically conditioned fear). Using factorial analyses of variance (ANOVAs) we aimed to analyse sex differences in anxiety and fear in this N/Nih-HS rat sample, as well as to assess the effects of (and interactions with) other independent factors, such as batch, season, coat colour and experimenter. Body weight was taken as a quantitative covariate and analysed by covariance analysis (ANCOVA). Obliquely-rotated factor analyses were also performed separately for each sex, in order to evaluate associations among the most relevant variables from each behavioural test and the common dimensions (i.e. factors) underlying the different behavioural responses. ANOVA analyses showed a consistent pattern of sex effects, with females showing less signs of anxiety and fear than males across all tests. There were also significant main effects of batch, season, colour and experimenter on almost all behavioural variables, as well as "sex × batch", "sex × season" and "sex × experimenter" interactions. Body weight showed significant effects in the ANCOVAs of most behavioural measures, but sex effects were still present in spite of (and after controlling for) these "body weight" effects. Factor analyses of relevant variables from each test showed a two-fold factor structure in both sexes, with the first factor mainly representing anxiety and conditioned fear in males, while in females the first factor was dominated by loadings of activity measures. Thus, besides showing consistent sex differences in anxiety-, fear- and activity-related responses in N/Nih-HS rats, the present study shows that females' behaviour is predominantly influenced by activity while males are more influenced by anxiety. Moreover, the results point out that, besides "sex" effects, physiological variables such as colour and body weight, and environmental factors as batch/season or "experimenter", have to be taken into account in both behavioural and quantitative genetic studies because of their demonstrated influences on phenotypic outcomes. Hide abstract
2012. Epilogue: Lessons from the CONVERGE study of major depressive disorder in China JOURNAL OF AFFECTIVE DISORDERS, 140 (1), | Read more
2011. Heterogeneous stock rat: A unique animal model for mapping genes influencing bone fragility BONE, 48 (5), | Read more
2011. Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women Journal of Affective Disorders,
2011. Clinical predictors of familial depression in Han Chinese women Depression and Anxiety, 4 (2),
2011. Childhood sexual abuse and the risk for recurrent major depression in Chinese women Psychological Medicine,
2011. The relationship between neuroticism, major depressive disorder and comorbid disorders in Chinese women Journal of Affective Disorders,
2011. Cytoarchitectural disruption of the superior colliculus and an enlarged acoustic startle response in the Tuba1a mutant mouse Neuroscience,
2012. Clinical features and risk factors for post-partum depression in a large cohort of Chinese women with recurrent major depressive disorder JOURNAL OF AFFECTIVE DISORDERS, 136 (3), | Read more
2011. Prioritization and Association Analysis of Murine-Derived Candidate Genes in Anxiety-Spectrum Disorders Biological Psychiatry,
2012. The impact of educational status on the clinical features of major depressive disorder among Chinese women JOURNAL OF AFFECTIVE DISORDERS, 136 (3), | Read more
2011. Age at onset of major depressive disorder in Han Chinese women: Relationship with clinical features and family history Journal of Affective Disorders,
2011. A comparison of melancholic and nonmelancholic recurrent major depression in Han Chinese women Depression and Anxiety, 4 (2),
2011. Dissecting the genetic architecture of human personality Trends in Cognitive Sciences,
2011. A comparison of the clinical characteristics of Chinese patients with recurrent major depressive disorder with and without dysthymia Journal of Affective Disorders,
2010. Association of the 5-HTTLPR genotype and unipolar depression: a meta-analysis PSYCHOLOGICAL MEDICINE, 40 (11), Read abstract | Read more
Background We sought to ascertain the strength of evidence for association between the 5-HTTLPR polymorphism and unipolar depression.Method We applied meta-analytic techniques to data from relevant published studies, and obtained an estimate of the likely magnitude of effect of any association. We also tested for possible publication bias, and explored the impact of various study design characteristics on the magnitude of the observed effect size.Results Meta-analysis indicated evidence of a small but statistically significant association between the 5-HTTLPR polymorphism and unipolar depression [odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03-1.12]. This remained significant when data from samples of European and East Asian ancestry were analyzed separately. In all cases there was evidence of significant between-study heterogeneity, although the observed associations were robust to the application of a random-effects framework.Conclusions Our results support the presence of a small effect of a polymorphism in the serotonin transporter promoter on susceptibility to depression. However, we caution that it is possible that the effect has an artifactual basis, rather than a biological origin. © 2010 Cambridge University Press. Hide abstract
2010. Inbred Mouse Strains with Complete Genome Sequences and Genetic Stability, a Powerful Tool Set for the Study of Human Disease JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE, 49 (5),
2011. Mapping quantitative traits and strategies to find quantitative trait genes. Methods, 53 (2), 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
2010. VIEWPOINT Missing heritability and strategies for finding the underlying causes of complex disease NATURE REVIEWS GENETICS, 11 (6), | Read more
2010. Tuba8 Is Expressed at Low Levels in the Developing Mouse and Human Brain AMERICAN JOURNAL OF HUMAN GENETICS, 86 (5), | Read more
2010. Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci U S A, 107 (7), Read abstract | Read more
CD8(+) T lymphocytes play a key role in host defense, in particular against important persistent viruses, although the critical functional properties of such cells in tissue are not fully defined. We have previously observed that CD8(+) T cells specific for tissue-localized viruses such as hepatitis C virus express high levels of the C-type lectin CD161. To explore the significance of this, we examined CD8(+)CD161(+) T cells in healthy donors and those with hepatitis C virus and defined a population of CD8(+) T cells with distinct homing and functional properties. These cells express high levels of CD161 and a pattern of molecules consistent with type 17 differentiation, including cytokines (e.g., IL-17, IL-22), transcription factors (e.g., retinoic acid-related orphan receptor gamma-t, P = 6 x 10(-9); RUNX2, P = 0.004), cytokine receptors (e.g., IL-23R, P = 2 x 10(-7); IL-18 receptor, P = 4 x 10(-6)), and chemokine receptors (e.g., CCR6, P = 3 x 10(-8); CXCR6, P = 3 x 10(-7); CCR2, P = 4 x 10(-7)). CD161(+)CD8(+) T cells were markedly enriched in tissue samples and coexpressed IL-17 with high levels of IFN-gamma and/or IL-22. The levels of polyfunctional cells in tissue was most marked in those with mild disease (P = 0.0006). These data define a T cell lineage that is present already in cord blood and represents as many as one in six circulating CD8(+) T cells in normal humans and a substantial fraction of tissue-infiltrating CD8(+) T cells in chronic inflammation. Such cells play a role in the pathogenesis of chronic hepatitis and arthritis and potentially in other infectious and inflammatory diseases of man. Hide abstract
2010. Commercially available outbred mice for genome-wide association studies. PLoS Genet, 6 (9), 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
2010. The Role of Tuba1a in Adult Hippocampal Neurogenesis and the Formation of the Dentate Gyrus DEVELOPMENTAL NEUROSCIENCE, 32 (4), Read abstract | Read more
The multitubulin hypothesis holds that each tubulin isotype serves a unique role with respect to microtubule function. Here we investigate the role of the α-tubulin subunit Tuba1a in adult hippocampal neurogenesis and the formation of the dentate gyrus. Employing birth date labelling and immunohistological markers, we show that mice harbouring an S140G mutation in Tuba1a present with normal neurogenic potential, but that this neurogenesis is often ectopic. Morphological analysis of the dentate gyrus in adulthood revealed a disorganised subgranular zone and a dispersed granule cell layer. We have shown that these anatomical abnormalities are due to defective migration of prospero-homeobox-1-positive neurons and T-box-brain-2-positive progenitors during development. Such migratory defects may also be responsible for the cytoarchitectural defects observed in the dentate gyrus of patients with mutations in TUBA1A. Copyright © 2010 S. Karger AG, Basel. Hide abstract
2010. Elusive copy number variation in the mouse genome. PLoS One, 5 (9), Read abstract | Read more
Array comparative genomic hybridization (aCGH) to detect copy number variants (CNVs) in mammalian genomes has led to a growing awareness of the potential importance of this category of sequence variation as a cause of phenotypic variation. Yet there are large discrepancies between studies, so that the extent of the genome affected by CNVs is unknown. We combined molecular and aCGH analyses of CNVs in inbred mouse strains to investigate this question. Hide abstract
2010. Association of the 5- HTTLPR genotype and unipolar depression: a meta-analysis Psychological Medicine,
2010. A genetic and functional relationship between T cells and cellular proliferation in the adult hippocampus. PLoS Biol, 8 (12), 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
2010. Defining Replication: A Response to Kaufman and Colleagues Biological Psychiatry, 67 (4), | Read more
2010. How reliable are scientific studies? BRITISH JOURNAL OF PSYCHIATRY, 197 (4), Read abstract | Read more
There is growing concern that a substantial proportion of scientific research may in fact be false. A number of factors have been proposed as contributing to the presence of a large number of false-positive results in the literature, one of which is publication bias. We discuss empirical evidence for these factors. Hide abstract
2009. Unlearned anxiety predicts learned fear: A comparison among heterogeneous rats and the Roman rat strains BEHAVIOURAL BRAIN RESEARCH, 202 (1), Read abstract | Read more
Anxiety-related behaviors were evaluated across five tests in a sample of 277 rats from a genetically heterogeneous stock (N/Nih-HS rats), derived from an eight-way cross of inbred strains, and compared with the performance of RLA-I (high anxious) and RHA-I (low anxious) rats in the same tests. These tests either evoke unlearned (novel-cage activity (NACT), elevated "zero" maze (ZM), baseline acoustic startle response (BAS)) or learned (fear-potentiated startle (FPS), two-way active-shuttle box-avoidance acquisition (SHAV)) anxious/fearful responses. The results overall showed that unlearned anxiety responses/behaviors were predictive of behavior in learned fear (i.e. fear-potentiated startle) and conflict (i.e. two-way active avoidance acquisition) situations. Moreover, it was found that N/Nih-HS rats either resemble RLA-I rat anxiety/fear scores or fall in between those of the RLA-I (high anxious) and the RHA-I (low anxious) rat strains. An additional regression analysis (of N/Nih-HS rat data) showed significant positive influences of (unlearned) baseline startle response, risk assessment (i.e. stretch-attend) behavior and activity (5 min) in a novel cage on SHAV acquisition, while baseline startle and entries into the open section of the elevated 'zero' maze test of anxiety were the main variables influencing FPS. This indicates that startle responses may have a facilitating role in the rat's active responses in the two-way active (shuttlebox) avoidance acquisition. The results of this behavioral evaluation of N/Nih-HS rats show that unconditioned anxiety (e.g. in the ZM test) predicts learned fear-related responses (e.g. FPS and SHAV) to some extent, while a positive association is also observed between BAS and SHAV. These findings are discussed in terms of their potential usefulness for present and future neurobehavioral and genetic studies of fearfulness/anxiety. © 2009 Elsevier B.V. Hide abstract
2009. Mapping in Structured Populations by Resample Model Averaging GENETICS, 182 (4), 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
2009. A New Standard Genetic Map for the Laboratory Mouse GENETICS, 182 (4), Read abstract | Read more
Genetic maps provide a means to estimate the probability of the co-inheritance of linked loci as they are transmitted across generations in both experimental and natural populations. However, in the age of whole-genome sequences, physical distances measured in base pairs of DNA provide the standard coordinates for navigating the myriad features of genomes. Although genetic and physical maps are colinear, there are well-characterized and sometimes dramatic heterogeneities in the average frequency of meiotic recombination events that occur along the physical extent of chromosomes. There also are documented differences in the recombination landscape between the two sexes. We have revisited high-resolution genetic map data from a large heterogeneous mouse population and have constructed a revised genetic map of the mouse genome, incorporating 10,195 single nucleotide polymorphisms using a set of 47 families comprising 3546 meioses. The revised map provides a different picture of recombination in the mouse from that reported previously. We have further integrated the genetic and physical maps of the genome and incorporated SSLP markers from other genetic maps into this new framework. We demonstrate that utilization of the revised genetic map improves QTL mapping, partially due to the resolution of previously undetected errors in marker ordering along the chromosome. Copyright © 2009 by the Genetics Society of America. Hide abstract
2009. Mapping in structured populations by resample model averaging. Genetics, 182 (4), 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. Hide abstract
2009. Replication and heterogeneity in gene x environment interaction studies INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 12 (6), | Read more
2009. High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues. Genome Res, 19 (6), 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
2009. Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria NATURE GENETICS, 41 (6), Read abstract | Read more
Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a Β-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations. Hide abstract
2009. Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res, 19 (5), 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
2009. Is there an association between NPY and neuroticism? Nature, 458 (7238), Read abstract | Read more
Psychiatric genetics has been hampered by the fact that initially exciting findings from underpowered studies are so often not replicated in larger, more powerful, data sets. Here we show that the claims of Zhou et al. that neuropeptide Y (NPY) diplotype-predicted expression is correlated with trait anxiety (neuroticism) is not replicated in a data set consisting of phenotypically extreme individuals drawn from a large (n = 88,142) non-clinical population. We found no association between NPY diplotype or diplotype-predicted expression and neuroticism. Our reply to Zhou and colleagues forms part of a larger debate (see, for example, http://www.nature.com/news/2008/080709/full/454154a.html) about the efficacy and replicability of candidate driven versus genome wide approaches to psychiatric genetics. Hide abstract
2009. 5-HTTLPR Genotype and Anxiety-Related Personality Traits: A Meta-Analysis and New Data AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 150B (2), Read abstract | Read more
We investigated the strength of evidence for association of the 5-HTTLPR polymorphism and the personality trait of Harm Avoidance. We used new primary data from a large sample of adults drawn from the Finnish population. We also applied meta-analytic techniques to synthesize existing published data. The large number of studies of the 5-HTTLPR polymorphism allowed us to apply a formal test of publication bias, as well as formally investigate the impact of potential moderating factors such as measurement instrument. Univariate ANOVA of primary data (n = 3,872), with 5-HTTLPR genotype as a between- groups factor, indicated no evidence of association with Harm Avoidance (P = 0.99). Meta-analysis indicated no evidence of significant association of 5-HTTLPR with Harm Avoidance (d = 0.02, P = 0.37), or EPQ Neuroticism (d = 0.01, P = 0.71), although there was evidence of association with NEO Neuroticism (d = 0.18, P< 0.001). Our analyses indicate that the 5-HTTLPR variant is not associated with Harm Avoidance. Together with our previous analyses of a large sample of participants with extreme Neuroticism scores (defined by the EPQ), we have data that excludes a meaningful genetic effect of the 5-HTTLPR on two measures of anxiety-related personality traits. There remains the possibility that the variant influences the NEO personality questionnaire measure of Neuroticism. However, a large, well-powered primary study is required to test this hypothesis directly and adequately. © 2008 Wiley-Liss, Inc. Hide abstract
2009. Genomewide SNP Screen to Detect Quantitative Trait Loci for Alcohol Preference in the High Alcohol Preferring and Low Alcohol Preferring Mice ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 33 (3), | Read more
2009. Bias in genetic association studies and impact factor MOLECULAR PSYCHIATRY, 14 (2), | Read more
2009. Gene x Environment Interactions at the Serotonin Transporter Locus BIOLOGICAL PSYCHIATRY, 65 (3), Read abstract | Read more
Background: Although it is universally accepted that human disease and behavior depend upon both environmental and genetic variation, a view supported by family and twin studies, examples of environmental interactions with genes identified at the molecular level (G × E) are not so well established. Methods: We carried out a systematic review and meta-analysis of the serotonin transporter (5-HTTLPR) polymorphic region × stressful life event (SLE) literature and investigated to what extent the main effects reported in this literature are consistent with a number of G × E hypotheses. Our aim was to provide a framework in which to assess the robustness of the claim for the presence of an interaction. Results: The results from our systematic review and meta-analysis indicate that the main effect of 5-HTTLPR genotype and the interaction effect between 5-HTTLPR and SLE on risk of depression are negligible. We found that only a minority of studies report a replication that is qualitatively comparable to that in the original report. Conclusions: Given reasonable assumptions regarding likely genetic and environmental effect sizes, our simulations indicate that published studies are underpowered. This, together with other aspects of the literature, leads us to suggest that the positive results for the 5-HTTLPR × SLE interactions in logistic regression models are compatible with chance findings. © 2009 Society of Biological Psychiatry. Hide abstract
2009. A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock. Genome Res, 19 (1), Read abstract | Read more
The laboratory rat (Rattus norvegicus) is a key tool for the study of medicine and pharmacology for human health. A large database of phenotypes for integrated fields such as cardiovascular, neuroscience, and exercise physiology exists in the literature. However, the molecular characterization of the genetic loci that give rise to variation in these traits has proven to be difficult. Here we show how one obstacle to progress, the fine-mapping of quantitative trait loci (QTL), can be overcome by using an outbred population of rats. By use of a genetically heterogeneous stock of rats, we map a locus contributing to variation in a fear-related measure (two-way active avoidance in the shuttle box) to a region on chromosome 5 containing nine genes. By establishing a protocol measuring multiple phenotypes including immunology, neuroinflammation, and hematology, as well as cardiovascular, metabolic, and behavioral traits, we establish the rat HS as a new resource for the fine-mapping of QTLs contributing to variation in complex traits of biomedical relevance. Hide abstract
2009. Ansiedad en ratas genéticamente heterogéneas: hacia la identificación de genes para caracteres conductuales cuantitativos Ansiedad y Estres, 15 (1), Read abstract
The use of genetically heterogeneous (outbred) rodents is a unique resource for the identification and fine mapping of genetic loci (QTL) influencing biological and behavioural quantitative phenotypes, allowing the identification of quantitative genes. We present the first study of this kind carried out with genetically heterogeneous rats (N/Nih-HS; derivated from an eight-way cross of inbred strains), whose behaviour is assessed in tests evoking unlearned (Black/white box, Elevated "zero" maze) or learned (context conditioned freezing, two-way active avoidance acquisition in the shuttlebox) anxious/fearful responses. The behavioural profile of N/Nih-HS rats is more similar to that of RLA-I (anxious) rats rather than to RHA-I (low anxious) rats. Significant correlations are found among unconditioned anxiety variables and two-way active avoidance acquisition in the shuttlebox; these are partially confirmed by multiple regression analysis. "High avoider" N/Nih-HS rats show lower unlearned anxiety levels than "low avoiders". Results of this behavioural assessment of the N/Nih-HS rats are discussed in terms of their potential usefulness for present and future neurobehavioural and genetic studies of fearfulness and anxiety. © Copyright 2009: de los Editores de Ansiedad y Estrés. Hide abstract
2008. Applying mouse complex-trait resources to behavioural genetics. Nature, 456 (7223), Read abstract | Read more
Studies of the genetic basis of behaviour in mice are at a turning point. Soon, new resources will enable the behavioural function of all genes to be tested and the networks of genes, messenger RNAs and proteins involved in a particular behaviour to be identified. Using these resources, scientists will be able to analyse mouse behaviour at an unprecedented level of detail. Interpreting the new data, however, will require a shift in focus from gene-based approaches to network-based approaches. Hide abstract
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