According to Oedegaard et al. (2010) the co-morbidity of migraine and bipolar disorder (BPD) is w... more According to Oedegaard et al. (2010) the co-morbidity of migraine and bipolar disorder (BPD) is well documented in numerous epidemiological and clinical studies, and there are clear pathophysiological similarities. Interestingly, in a genome-wide scan, Lea et al. (2005) identified a susceptibility locus for a severe heritable form of common migraine on chromosome 3q29. With respect to BPD, a susceptibility region on chromosome 3q29 was identified in a genome-wide linkage scan (Bailer et al. 2002) and follow-up linkage analysis (Schosser et al. 2004). These findings were also supported by further fine-mapping of this region (Schosser et al. 2007). Since 3q29 is among the chromosomal regions implicated in migraine and bipolar linkage studies, the aim of the current study is to test for 3q29 association of migraine in sample of patients with BPD. The sample consists of 463 patients with a diagnosis of BPD (34.63% men, 65.37% women; mean age ± SD: 48.01 ± 11.26), as defined by the Diagn...
A cDNA clone (p422) containing about 200bp of coding sequences for steroid sulphatase (STS) has b... more A cDNA clone (p422) containing about 200bp of coding sequences for steroid sulphatase (STS) has been isolated from a lambda gt11 expression library by antibody screening and has been assigned by mapping with a somatic cell hybrid panel and by in situ hybridization to Xp22.3; a localization coincident with the previously identified locus for STS expression. Although no significant hybridization of this clone to the Y chromosome was observed, p422 has been used to isolate a longer cDNA clone and genomic sequences which do recognize Y-specific restriction fragments. An abbreviated STS gene has been localized to Yq11.2. The coding sequences for the human enzyme shows little homology to sequences in mice.
Background: It has been suggested that outcomes of antidepressant treatment for major depressive ... more Background: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. Methods and Findings: The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p,5610 28). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p,5610 28) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. Conclusions: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study.
DNA diagnosis of X-linked retinitis pigmentosa (XLRP) is hampered by its genetic heterogeneity, w... more DNA diagnosis of X-linked retinitis pigmentosa (XLRP) is hampered by its genetic heterogeneity, while a clinical subdivision is almost impossible to make. So far, diagnostic services have been offered only to those families in which linkage to one RP locus (RP2 or RP3) has been clearly established. In most families, however, the nature of the XLRP type cannot be distinguished on the basis of linkage analysis. Here the authors describe that in some families DNA diagnosis is nonetheless feasible, when polymorphic DNA markers are used which span the entire Xp21.1-Xcen region and when no recombination between these markers disturbs the phase.
is a full time employee of Roche. Domenici was full time employee of Glaxo-Smith Kline when he un... more is a full time employee of Roche. Domenici was full time employee of Glaxo-Smith Kline when he undertook work on this study. Hall and Wendland are full time employees of Pfizer. Wendland was full time employee of Roche when this work began. Henigsberg has participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck and received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck.
It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulat... more It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulation of mood. Three studies have reported linkage on chromosome 7 with major depressive disorder (MDD) in or close to a region containing the muscarinic receptor CHRM2 gene. A ...
The serotonergic system consists of a number of genes and includes seven subfamilies of serotonin... more The serotonergic system consists of a number of genes and includes seven subfamilies of serotonin receptors (5-HT1-7), with each subfamily revealing several subtypes. The system also includes tryptophan hydroxylase (TPH-1 and TPH-2) and monoamine oxidase (MAO) enzymes which are involved in synthesis and degradation of serotonin, respectively. Furthermore, serotonin transporter (SERT, 5-HTT) is an important protein in the scheme as
In this study, we present a pharmacoproteomic investigation of response to antidepressants two in... more In this study, we present a pharmacoproteomic investigation of response to antidepressants two inbred strains. Our aim was to uncover molecular mechanisms underlying antidepressant action and identify new biomarkers to determine therapeutic response to two antidepressants with proven efficacy in the treatment of depression but divergent mechanisms of action. Mice were treated with the pro-noradrenergic drug nortriptyline, the pro-serotonergic drug escitalopram or saline. Quantitative proteomic analyses were undertaken on hippocampal tissue from a study design that used two inbred mouse strains, two depressogenic protocols and a control condition, (maternal separation, chronic mild stress, control), two antidepressant drugs and two dosing protocols. The proteomic analysis was aimed at the identification of specific drug-response markers. Complementary approaches, 2DE and isobaric tandem mass tagging (TMT), were applied to the selected experimental groups. To investigate the relationship between proteomic profiles, depressogenic protocols and drug response, 2DE and TMT data sets were analysed using multivariate methods. The results highlighted significant strain-and stress-related differences across both 2DE and TMT data sets and identified the three gene products involved in serotonergic (PXBD5, YHWAB, SLC25A4) and one in noradrenergic antidepressant action (PXBD6).
Genetic association studies provide considerable evidence that the 10-repeat allele of a variable... more Genetic association studies provide considerable evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in the 3 0-untranslated region (3 0-UTR) of the dopamine transporter gene (DAT1) is associated with a range of psychiatric phenotypes, most notably, attention deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe, and lymphocytes using quantitative real-time reverse-transcription polymerase chain reaction. Relative to a set of four control housekeeping genes (b-actin, GAPD, ribosomal 18S, and b2-microglobulin) we observed that increased levels of DAT1 expression were associated with the number of 10-repeat alleles. These data provide direct evidence that the VNTR, or another polymorphism in linkage disequilibrium with the VNTR, is involved in regulating expression of this gene.
A consideration of the evolutionary, physiological and anthropological aspects of aggression sugg... more A consideration of the evolutionary, physiological and anthropological aspects of aggression suggests that individual diVerences in such behaviour will have important genetic as well as environmental underpinning. Surveys of the likely pathways controlling the physiological and neuronal processes involved highlight, as obvious targets to investigate, genes implicated in sexual diVerentiation, anxiety, stress response and the serotonin neurotransmitter pathway. To date, however, association studies on single candidates have provided little evidence for any such loci with a major eVect size. This may be because genes do not operate independently, but function against a background in which other genetic and environmental factors are crucial. Indeed, a series of recent studies, particularly concentrating on the serotonin and norepinephrine metabolising enzyme, monoamine oxidase A, has emphasised the necessity of examining gene by environmental interactions if the contributions of individual loci are to be understood. These Wndings will have major signiWcance for the interpretation and analysis of data from detailed whole genome association studies. Functional imaging studies of genetic variants aVecting serotonin pathways have also provided valuable insights into potential links between genes, brain and aggressive behaviour.
Both childhood maltreatment and adult stressful life events are established risk factors for the ... more Both childhood maltreatment and adult stressful life events are established risk factors for the onset of depression in adulthood. However, the interaction between them can be viewed through two conflicting frameworks. Under a mismatch hypothesis stressful childhoods allow 'adaptive programming' for a stressful adulthood and so can be protective. Only when childhood and adulthood do not match is there a risk of behavioural problems. Alternatively, under the cumulative stress hypothesis we expect increased risk with each additional stressor. It has also been suggested that an individual's genetic background may determine the extent they undergo adaptive programming, and so which of these two hypotheses is relevant. In this study we test for an interaction between exposure to childhood maltreatment and adult stressful life events in a retrospective sample of 455 individuals, using major depression as the outcome. We also test whether this interaction differs by genotype at the 5-HTTLPR, a candidate for an individual's plasticity to adaptive programming. Early maltreatment and stressful life events in adulthood interacted to produce increased risk for depression over each individually (p ¼ 0.055). This supports the cumulative stress hypothesis over the mismatch hypothesis, at least with respect to severe environmental risk factors. This effect was not altered by 5-HTTLPR allele, suggesting there was no difference by genotype in adaptive programming to these events. We suggest that the apparent additional vulnerability to stressful events of those who have experienced maltreatment has clinical relevance, highlighting the importance of providing support beyond the immediate aftermath of maltreatment into adulthood.
According to Oedegaard et al. (2010) the co-morbidity of migraine and bipolar disorder (BPD) is w... more According to Oedegaard et al. (2010) the co-morbidity of migraine and bipolar disorder (BPD) is well documented in numerous epidemiological and clinical studies, and there are clear pathophysiological similarities. Interestingly, in a genome-wide scan, Lea et al. (2005) identified a susceptibility locus for a severe heritable form of common migraine on chromosome 3q29. With respect to BPD, a susceptibility region on chromosome 3q29 was identified in a genome-wide linkage scan (Bailer et al. 2002) and follow-up linkage analysis (Schosser et al. 2004). These findings were also supported by further fine-mapping of this region (Schosser et al. 2007). Since 3q29 is among the chromosomal regions implicated in migraine and bipolar linkage studies, the aim of the current study is to test for 3q29 association of migraine in sample of patients with BPD. The sample consists of 463 patients with a diagnosis of BPD (34.63% men, 65.37% women; mean age ± SD: 48.01 ± 11.26), as defined by the Diagn...
A cDNA clone (p422) containing about 200bp of coding sequences for steroid sulphatase (STS) has b... more A cDNA clone (p422) containing about 200bp of coding sequences for steroid sulphatase (STS) has been isolated from a lambda gt11 expression library by antibody screening and has been assigned by mapping with a somatic cell hybrid panel and by in situ hybridization to Xp22.3; a localization coincident with the previously identified locus for STS expression. Although no significant hybridization of this clone to the Y chromosome was observed, p422 has been used to isolate a longer cDNA clone and genomic sequences which do recognize Y-specific restriction fragments. An abbreviated STS gene has been localized to Yq11.2. The coding sequences for the human enzyme shows little homology to sequences in mice.
Background: It has been suggested that outcomes of antidepressant treatment for major depressive ... more Background: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. Methods and Findings: The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p,5610 28). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p,5610 28) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. Conclusions: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study.
DNA diagnosis of X-linked retinitis pigmentosa (XLRP) is hampered by its genetic heterogeneity, w... more DNA diagnosis of X-linked retinitis pigmentosa (XLRP) is hampered by its genetic heterogeneity, while a clinical subdivision is almost impossible to make. So far, diagnostic services have been offered only to those families in which linkage to one RP locus (RP2 or RP3) has been clearly established. In most families, however, the nature of the XLRP type cannot be distinguished on the basis of linkage analysis. Here the authors describe that in some families DNA diagnosis is nonetheless feasible, when polymorphic DNA markers are used which span the entire Xp21.1-Xcen region and when no recombination between these markers disturbs the phase.
is a full time employee of Roche. Domenici was full time employee of Glaxo-Smith Kline when he un... more is a full time employee of Roche. Domenici was full time employee of Glaxo-Smith Kline when he undertook work on this study. Hall and Wendland are full time employees of Pfizer. Wendland was full time employee of Roche when this work began. Henigsberg has participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck and received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck.
It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulat... more It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulation of mood. Three studies have reported linkage on chromosome 7 with major depressive disorder (MDD) in or close to a region containing the muscarinic receptor CHRM2 gene. A ...
The serotonergic system consists of a number of genes and includes seven subfamilies of serotonin... more The serotonergic system consists of a number of genes and includes seven subfamilies of serotonin receptors (5-HT1-7), with each subfamily revealing several subtypes. The system also includes tryptophan hydroxylase (TPH-1 and TPH-2) and monoamine oxidase (MAO) enzymes which are involved in synthesis and degradation of serotonin, respectively. Furthermore, serotonin transporter (SERT, 5-HTT) is an important protein in the scheme as
In this study, we present a pharmacoproteomic investigation of response to antidepressants two in... more In this study, we present a pharmacoproteomic investigation of response to antidepressants two inbred strains. Our aim was to uncover molecular mechanisms underlying antidepressant action and identify new biomarkers to determine therapeutic response to two antidepressants with proven efficacy in the treatment of depression but divergent mechanisms of action. Mice were treated with the pro-noradrenergic drug nortriptyline, the pro-serotonergic drug escitalopram or saline. Quantitative proteomic analyses were undertaken on hippocampal tissue from a study design that used two inbred mouse strains, two depressogenic protocols and a control condition, (maternal separation, chronic mild stress, control), two antidepressant drugs and two dosing protocols. The proteomic analysis was aimed at the identification of specific drug-response markers. Complementary approaches, 2DE and isobaric tandem mass tagging (TMT), were applied to the selected experimental groups. To investigate the relationship between proteomic profiles, depressogenic protocols and drug response, 2DE and TMT data sets were analysed using multivariate methods. The results highlighted significant strain-and stress-related differences across both 2DE and TMT data sets and identified the three gene products involved in serotonergic (PXBD5, YHWAB, SLC25A4) and one in noradrenergic antidepressant action (PXBD6).
Genetic association studies provide considerable evidence that the 10-repeat allele of a variable... more Genetic association studies provide considerable evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in the 3 0-untranslated region (3 0-UTR) of the dopamine transporter gene (DAT1) is associated with a range of psychiatric phenotypes, most notably, attention deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe, and lymphocytes using quantitative real-time reverse-transcription polymerase chain reaction. Relative to a set of four control housekeeping genes (b-actin, GAPD, ribosomal 18S, and b2-microglobulin) we observed that increased levels of DAT1 expression were associated with the number of 10-repeat alleles. These data provide direct evidence that the VNTR, or another polymorphism in linkage disequilibrium with the VNTR, is involved in regulating expression of this gene.
A consideration of the evolutionary, physiological and anthropological aspects of aggression sugg... more A consideration of the evolutionary, physiological and anthropological aspects of aggression suggests that individual diVerences in such behaviour will have important genetic as well as environmental underpinning. Surveys of the likely pathways controlling the physiological and neuronal processes involved highlight, as obvious targets to investigate, genes implicated in sexual diVerentiation, anxiety, stress response and the serotonin neurotransmitter pathway. To date, however, association studies on single candidates have provided little evidence for any such loci with a major eVect size. This may be because genes do not operate independently, but function against a background in which other genetic and environmental factors are crucial. Indeed, a series of recent studies, particularly concentrating on the serotonin and norepinephrine metabolising enzyme, monoamine oxidase A, has emphasised the necessity of examining gene by environmental interactions if the contributions of individual loci are to be understood. These Wndings will have major signiWcance for the interpretation and analysis of data from detailed whole genome association studies. Functional imaging studies of genetic variants aVecting serotonin pathways have also provided valuable insights into potential links between genes, brain and aggressive behaviour.
Both childhood maltreatment and adult stressful life events are established risk factors for the ... more Both childhood maltreatment and adult stressful life events are established risk factors for the onset of depression in adulthood. However, the interaction between them can be viewed through two conflicting frameworks. Under a mismatch hypothesis stressful childhoods allow 'adaptive programming' for a stressful adulthood and so can be protective. Only when childhood and adulthood do not match is there a risk of behavioural problems. Alternatively, under the cumulative stress hypothesis we expect increased risk with each additional stressor. It has also been suggested that an individual's genetic background may determine the extent they undergo adaptive programming, and so which of these two hypotheses is relevant. In this study we test for an interaction between exposure to childhood maltreatment and adult stressful life events in a retrospective sample of 455 individuals, using major depression as the outcome. We also test whether this interaction differs by genotype at the 5-HTTLPR, a candidate for an individual's plasticity to adaptive programming. Early maltreatment and stressful life events in adulthood interacted to produce increased risk for depression over each individually (p ¼ 0.055). This supports the cumulative stress hypothesis over the mismatch hypothesis, at least with respect to severe environmental risk factors. This effect was not altered by 5-HTTLPR allele, suggesting there was no difference by genotype in adaptive programming to these events. We suggest that the apparent additional vulnerability to stressful events of those who have experienced maltreatment has clinical relevance, highlighting the importance of providing support beyond the immediate aftermath of maltreatment into adulthood.
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Papers by I. Craig