ORCID Profile
0000-0002-9427-4429
Current Organisations
University of California Los Angeles
,
University of Oxford
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Publisher: Cold Spring Harbor Laboratory
Date: 11-10-2018
DOI: 10.1101/440735
Abstract: Minimal phenotyping refers to the reliance on the use of a small number of self-report items for disease case identification. This strategy has been applied to genome-wide association studies (GWAS) of major depressive disorder (MDD). Here we report that the genotype derived heritability (h 2 SNP ) of depression defined by minimal phenotyping (14%, SE = 0.8%) is lower than strictly defined MDD (26%, SE = 2.2%). This cannot be explained by differences in prevalence between definitions or including cases of lower liability to MDD in minimal phenotyping definitions of depression, but can be explained by misdiagnosis of those without depression or with related conditions as cases of depression. Depression defined by minimal phenotyping is as genetically correlated with strictly defined MDD (rG = 0.81, SE = 0.03) as it is with the personality trait neuroticism (rG = 0.84, SE = 0.05), a trait not defined by the cardinal symptoms of depression. While they both show similar shared genetic liability with neuroticism, a greater proportion of the genome contributes to the minimal phenotyping definitions of depression (80.2%, SE = 0.6%) than to strictly defined MDD (65.8%, SE = 0.6%). We find that GWAS loci identified in minimal phenotyping definitions of depression are not specific to MDD: they also predispose to other psychiatric conditions. Finally, while highly predictive polygenic risk scores can be generated from minimal phenotyping definitions of MDD, the predictive power can be explained entirely by the s le size used to generate the polygenic risk score, rather than specificity for MDD. Our results reveal that genetic analysis of minimal phenotyping definitions of depression identifies non-specific genetic factors shared between MDD and other psychiatric conditions. Reliance on results from minimal phenotyping for MDD may thus bias views of the genetic architecture of MDD and may impede our ability to identify pathways specific to MDD.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2008
DOI: 10.1038/NG.147
Abstract: The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research.
Publisher: Oxford University Press (OUP)
Date: 16-06-2005
DOI: 10.1093/NAR/GKI643
Publisher: Elsevier BV
Date: 2016
Publisher: Hindawi Limited
Date: 11-2007
DOI: 10.1002/HUMU.20572
Abstract: We have recently reported a missense mutation in exon 4 of the tubulin alpha 1A (Tuba1a) gene in a hyperactive N-ethyl-N-nitrosourea (ENU) induced mouse mutant with abnormal lamination of the hippoc us. Neuroanatomical similarities between the Tuba1a mutant mouse and mice deficient for Doublecortin (Dcx) and Lis1 genes, and the well-established functional interaction between DCX and microtubules (MTs), led us to hypothesize that mutations in TUBA1A (TUBA3, previous symbol), the human homolog of Tuba1a, might give rise to cortical malformations. This hypothesis was subsequently confirmed by the identification of TUBA1A mutations in two patients with lissencephaly and pachygyria, respectively. Here we report additional TUBA1A mutations identified in six unrelated patients with a large spectrum of brain dysgeneses. The de novo occurrence was shown for all mutations, including one recurrent mutation (c.790C>T, p.R264C) detected in two patients, and two mutations that affect the same amino acid (c.1205G>A, p.R402H c.1204C>T, p.R402C) detected in two other patients. Retrospective examination of MR images suggests that patients with TUBA1A mutations share not only cortical dysgenesis, but also cerebellar, hippoc al, corpus callosum, and brainstem abnormalities. Interestingly, the specific high level of Tuba1a expression throughout the period of central nervous system (CNS) development, shown by in situ hybridization using mouse embryos, is in accordance with the brain-restricted developmental phenotype caused by TUBA1A mutations. All together, these results, in combination with previously reported data, strengthen the relevance of the known interaction between MTs and DCX, and highlight the importance of the MTs/DCX complex in the neuronal migration process.
Publisher: Public Library of Science (PLoS)
Date: 14-12-2010
Publisher: Springer Science and Business Media LLC
Date: 17-10-2004
DOI: 10.1038/NG1450
Abstract: 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 sub ided 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.
Publisher: Springer Science and Business Media LLC
Date: 04-2003
DOI: 10.1007/S00335-002-3059-5
Abstract: Fear conditioning is one of a number of models for investigating the genetic basis of in idual variation in emotion and learning. Genetic mapping using crosses between strains of laboratory mice has identified a locus on chromosome one that appears to influence not only variation in conditioned fear, but also in other validated tests of fear-related behaviour, (including the open-field and the elevated-plus maze), suggesting that the rodent locus may act in ways consistent with how a locus influencing susceptibility to anxiety in humans is believed to operate. Here we use high-resolution mapping in genetically heterogeneous mice to show that a quantitative trait locus influencing conditioned fear can be separated from loci influencing open-field activity. Mapping in two different heterogeneous stocks, the Boulder and Northport HS, gave similar map locations for open-field activity at two positions on the current mouse physical map, one at 162 Mb on chromosome one (negative log P-value 5.4) the other at 173 Mb (negative log P-value 4.8), while mapping of contextual conditioned fear in the Boulder HS identified a locus at 170 Mb (negative log P-value 5.4). Estimates of the 95% confidence intervals show that the locations do not overlap. The region containing a gene or genes that influence variation in conditioned fear is approximately 1 megabase in size and contains only one gene of known function, a pre-B cell leukaemia factor.
Publisher: Elsevier BV
Date: 2007
Publisher: Elsevier BV
Date: 07-2013
Publisher: Elsevier BV
Date: 2016
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1086/374178
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.BIOPSYCH.2005.05.014
Abstract: The val66met variant located within the brain-derived neurotrophic factor gene (BDNF) has previously been associated with human neuroticism, a dimension of personality strongly predictive of depressive illness. Here we report an attempt to replicate this association using three populations of extreme neuroticism scorers derived from two large English cohorts (n = 88,142 and n = 20,921). On the basis of the current literature, which indicates that an effect of BDNF may only become apparent in those in iduals exposed to stress, a gene-environment interaction was also sought. No statistically significant effects were identified, although simulations indicated that the s les held sufficient power to detect a main effect accounting for just .75% of variation and an interaction accounting for 4% of variation. These data do not support the hypothesis that the val66met BDNF polymorphism contributes toward variation in the human personality trait neuroticism, at least as indexed by the Eysenck Personality Questionnaire.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jonathan Flint.