26 results on '"Cook, Edwin H."'
Search Results
2. Maternal Serotonin Levels Are Associated With Cognitive Ability and Core Symptoms in Autism Spectrum Disorder.
- Author
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Montgomery AK, Shuffrey LC, Guter SJ, Anderson GM, Jacob S, Mosconi MW, Sweeney JA, Turner JB, Sutcliffe JS, Cook EH Jr, and Veenstra-VanderWeele J
- Subjects
- Adult, Autism Spectrum Disorder blood, Autism Spectrum Disorder genetics, Biomarkers blood, Child, Fathers, Female, Humans, Male, Neuropsychological Tests, Prospective Studies, Autism Spectrum Disorder physiopathology, Cognition physiology, Mothers statistics & numerical data, Serotonin blood
- Abstract
Objective: The serotonin (5-hydroxytryptamine [HT]) system has long been implicated in autism spectrum disorder (ASD). Whole-blood 5-HT level (WB5-HT) is a stable, heritable biomarker that is elevated in more than 25% of children with ASD. Recent findings indicate that the maternal 5-HT system may influence embryonic neurodevelopment, but maternal WB5-HT has not been examined in relation to ASD phenotypes., Method: WB5-HT levels were obtained from 181 individuals (3-27 years of age) diagnosed with ASD, 99 of their fathers, and 119 of their mothers. Standardized assessments were used to evaluate cognitive, behavioral, and language phenotypes., Results: Exploratory regression analyses found relationships between maternal WB5-HT and nonverbal IQ (NVIQ), Autism Diagnostic Interview-Revised (ADI-R) Nonverbal Communication Algorithm scores, and overall adaptive function on the Vineland Adaptive Behavior Scales-II. Latent class analysis identified a three-class structure in the assessment data, describing children with low, intermediate, and high severity across measures of behavior, cognition, and adaptive function. Mean maternal WB5-HT differed across classes, with the lowest maternal WB5-HT levels seen in the highest-severity group (Welch F
2,46.048 = 17.394, p < .001). Paternal and proband WB5-HT did not differ between classes., Conclusion: Maternal WB5-HT is associated with neurodevelopmental outcomes in offspring with ASD. Prospective, longitudinal studies will be needed to better understand the relationship between the function of the maternal serotonin system during pregnancy and brain development. Further studies in animal models may be able to reveal the mechanisms underlying these findings., (Copyright © 2018 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
3. Is there sexual dimorphism of hyperserotonemia in autism spectrum disorder?
- Author
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Shuffrey LC, Guter SJ, Delaney S, Jacob S, Anderson GM, Sutcliffe JS, Cook EH, and Veenstra-VanderWeele J
- Subjects
- Biomarkers blood, Child, Female, Humans, Male, Risk, Sex Factors, Autism Spectrum Disorder blood, Serotonin blood, Sex Characteristics
- Abstract
Approximately 30% of individuals with autism spectrum disorder (ASD) have elevated whole blood serotonin (5-HT) levels. Genetic linkage and association studies of ASD and of whole blood 5-HT levels as a quantitative trait have revealed sexual dimorphism. Few studies have examined the presence of a sex difference on hyperserotonemia within ASD. To assess whether the rate of hyperserotonemia is different in males than in females with ASD, we measured whole blood 5-HT levels in 292 children and adolescents with ASD, the largest sample in which this biomarker has been assessed. Based upon previous work suggesting that hyperserotonemia is more common prior to puberty, we focused our analysis on the 182 pre-pubertal children with ASD. 42% of pre-pubertal participants were within the hyperserotonemia range. In this population, we found that males were significantly more likely to manifest hyperserotonemia than females (P = 0.03). As expected, no significant difference was found in the post-pubertal population. Additional work will be needed to replicate this intriguing finding and to understand whether it could potentially explain differences in patterns of ASD risk between males and females. Autism Res 2017, 10: 1417-1423. © 2017 International Society for Autism Research, Wiley Periodicals, Inc., (© 2017 International Society for Autism Research, Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
4. Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.
- Author
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Chen R, Davis LK, Guter S, Wei Q, Jacob S, Potter MH, Cox NJ, Cook EH, Sutcliffe JS, and Li B
- Subjects
- Autism Spectrum Disorder metabolism, Endophenotypes blood, Exome, Female, Genetic Predisposition to Disease, Humans, Male, Sequence Analysis, DNA methods, Signal Transduction, Autism Spectrum Disorder genetics, Forkhead Transcription Factors genetics, Jumonji Domain-Containing Histone Demethylases genetics, Mutation, Nuclear Proteins genetics, Repressor Proteins genetics, Serotonin blood, Ubiquitin-Specific Proteases genetics
- Abstract
Background: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown., Methods: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements., Results: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs ( FOXP1 and KDM5B ). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD., Conclusions: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes.
- Published
- 2017
- Full Text
- View/download PDF
5. Examining autism spectrum disorders by biomarkers: example from the oxytocin and serotonin systems.
- Author
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Hammock E, Veenstra-VanderWeele J, Yan Z, Kerr TM, Morris M, Anderson GM, Carter CS, Cook EH, and Jacob S
- Subjects
- Age Factors, Animals, Child, Female, Genotype, Humans, Male, Mice, Normal Distribution, Receptors, Oxytocin genetics, Biomarkers blood, Child Development Disorders, Pervasive diagnosis, Child Development Disorders, Pervasive physiopathology, Oxytocin blood, Serotonin blood
- Abstract
Objective: Autism spectrum disorder (ASD) is a heritable but highly heterogeneous neuropsychiatric syndrome, which poses challenges for research relying solely on behavioral symptoms or diagnosis. Examining biomarkers may give us ways to identify individuals who demonstrate specific developmental trajectories and etiological factors related to ASD. Plasma oxytocin (OT) and whole-blood serotonin (5-HT) levels are consistently altered in some individuals with ASD. Reciprocal relationships have been described between brain oxytocin and serotonin systems during development. We therefore investigated the relationship between these peripheral biomarkers as well as their relationships with age., Method: In our first study, we analyzed correlations between these two biomarkers in 31 children and adolescents who were diagnosed with autism and were not on medications. In our second study, we explored whether whole-blood 5-HT levels are altered in mice lacking the oxytocin receptor gene Oxtr., Results: In humans, OT and 5-HT were negatively correlated with each other (p < .05) and this relationship was most prominent in children less than 11 years old. Paralleling human findings, mice lacking Oxtr showed increased whole-blood 5-HT levels (p = .05), with this effect driven exclusively by mice less than 4 months old (p < .01)., Conclusions: Identifying relationships between identified ASD biomarkers may be a useful approach to connect otherwise disparate findings that span multiple systems in this heterogeneous disorder. Using neurochemical biomarkers to perform parallel studies in animal and human populations within a developmental context is a plausible approach to probe the root causes of ASD and to identify potential interventions., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
6. Relationship between whole blood serotonin and repetitive behaviors in autism.
- Author
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Kolevzon A, Newcorn JH, Kryzak L, Chaplin W, Watner D, Hollander E, Smith CJ, Cook EH Jr, and Silverman JM
- Subjects
- Adolescent, Autistic Disorder blood, Child, Child, Preschool, Female, Humans, Male, Psychiatric Status Rating Scales, Self-Injurious Behavior blood, Self-Injurious Behavior etiology, Autistic Disorder complications, Cumulative Trauma Disorders blood, Cumulative Trauma Disorders etiology, Serotonin blood
- Abstract
This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated., (2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
7. Serotonin rising.
- Author
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Anderson GM, Cook EH Jr, and Blakely RD
- Subjects
- Animals, Blood Platelets metabolism, Bone Remodeling physiology, Mice, Mice, Knockout, Osteoporosis metabolism, Receptors, Serotonin metabolism, Serotonin metabolism, Bone and Bones metabolism, Serotonin blood
- Published
- 2009
- Full Text
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8. Interactions between integrin alphaIIbbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans.
- Author
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Carneiro AM, Cook EH, Murphy DL, and Blakely RD
- Subjects
- Alleles, Animals, Biological Transport, Cell Line, Cell Membrane metabolism, Humans, MAP Kinase Signaling System, Mice, Mice, Knockout, Platelet Glycoprotein GPIIb-IIIa Complex genetics, Protein Binding, Protein Phosphatase 1 metabolism, Protein Phosphatase 2 metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Blood Platelets cytology, Blood Platelets metabolism, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Serotonin metabolism, Serotonin Plasma Membrane Transport Proteins metabolism
- Abstract
The essential contribution of the antidepressant-sensitive serotonin (5-HT) transporter SERT (which is encoded by the SLC6A4 gene) to platelet 5-HT stores suggests an important role of this transporter in platelet function. Here, using SERT-deficient mice, we have established a role for constitutive SERT expression in efficient ADP- and thrombin-triggered platelet aggregation. Additionally, using pharmacological blockers of SERT and the vesicular monoamine transporter (VMAT), we have identified a role for ongoing 5-HT release and SERT activity in efficient human platelet aggregation. We have also demonstrated that fibrinogen, an activator of integrin alphaIIbbeta3, enhances SERT activity in human platelets and that integrin alphaIIbbeta3 interacts directly with the C terminus of SERT. Consistent with these findings, knockout mice lacking integrin beta3 displayed diminished platelet SERT activity. Conversely, HEK293 cells engineered to express human SERT and an activated form of integrin beta3 exhibited enhanced SERT function that coincided with elevated SERT surface expression. Our results support an unsuspected role of alphaIIbbeta3/SERT associations as well as alphaIIbbeta3 activation in control of SERT activity in vivo that may have broad implications for hyperserotonemia, cardiovascular disorders, and autism.
- Published
- 2008
- Full Text
- View/download PDF
9. Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism.
- Author
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Cross S, Kim SJ, Weiss LA, Delahanty RJ, Sutcliffe JS, Leventhal BL, Cook EH Jr, and Veenstra-Vanderweele J
- Subjects
- Adult, Asian People genetics, Autistic Disorder blood, Black People genetics, DNA Primers, Female, Hispanic or Latino genetics, Humans, Male, Nuclear Family, Platelet Count, Serotonin Plasma Membrane Transport Proteins genetics, White People genetics, Autistic Disorder genetics, Blood Platelets physiology, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Serotonin blood
- Abstract
Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K(m), p=0.005) and 5-HT uptake rate (V(max), p=0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p=0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.
- Published
- 2008
- Full Text
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10. Association studies of serotonin system candidate genes in early-onset obsessive-compulsive disorder.
- Author
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Dickel DE, Veenstra-VanderWeele J, Bivens NC, Wu X, Fischer DJ, Van Etten-Lee M, Himle JA, Leventhal BL, Cook EH Jr, and Hanna GL
- Subjects
- Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Brain-Derived Neurotrophic Factor genetics, Child, Child, Preschool, DNA genetics, DNA isolation & purification, Female, Genotype, Humans, Linkage Disequilibrium genetics, Male, Middle Aged, Obsessive-Compulsive Disorder epidemiology, Polymorphism, Genetic genetics, Polymorphism, Single Nucleotide, Psychiatric Status Rating Scales, Receptor, Serotonin, 5-HT1B genetics, Receptor, Serotonin, 5-HT2A genetics, Reverse Transcriptase Polymerase Chain Reaction, Serotonin Plasma Membrane Transport Proteins genetics, Sex Factors, Tic Disorders epidemiology, Tourette Syndrome epidemiology, Tourette Syndrome genetics, Obsessive-Compulsive Disorder genetics, Obsessive-Compulsive Disorder physiopathology, Serotonin genetics, Serotonin physiology
- Abstract
Background: Family-based evidence for association at serotonin system genes SLC6A4, HTR1B, HTR2A, and brain-derived neurotrophic factor (BDNF) has been previously reported in obsessive-compulsive disorder (OCD). Early-onset OCD is a more familial form of the disorder., Methods: We used the transmission-disequilibrium test of association at common polymorphisms in each of these genes in 54 parent-child trios ascertained through probands with early-onset OCD., Results: No evidence for association was detected at any of the polymorphisms in the entire set of subjects. Nominally significant association was found at the HTR2A rs6311 polymorphism in subjects with tic disorder and OCD (p = .05), replicating a previous finding in Tourette syndrome and OCD. Nominally significant association was also found for the SLC6A4 HT transporter gene-linked polymorphic region (5-HTTLPR) polymorphism for female subjects (p = .03). Neither association would remain significant after statistical correction for multiple testing. Despite no individual study reporting replication, a pooled analysis of five replication studies of the SLC6A4 5-HTTLPR polymorphism supports association (p = .02)., Conclusions: Low power across individual association studies in OCD may lead to a false acceptance of the null hypothesis. Accumulation of evidence from multiple studies will be necessary to evaluate the potential role for these genes in contributing to susceptibility to OCD.
- Published
- 2007
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11. Variation in ITGB3 is associated with whole-blood serotonin level and autism susceptibility.
- Author
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Weiss LA, Kosova G, Delahanty RJ, Jiang L, Cook EH, Ober C, and Sutcliffe JS
- Subjects
- Alleles, Case-Control Studies, Female, Founder Effect, Genetic Predisposition to Disease, Humans, Male, Pedigree, Polymorphism, Single Nucleotide, Sex Factors, Autistic Disorder genetics, Genetic Variation, Integrin beta3 genetics, Quantitative Trait Loci, Serotonin blood
- Abstract
Autism is a pervasive developmental disorder affecting more males than females. Heritability estimates for autism can rise above 90%, and genes influencing the serotonin system are strong candidates for autism susceptibility genes, as drugs selectively acting on the serotonin system are some of the most effective treatments for maladaptive behaviors seen in autism. ITGB3 was recently identified as a male quantitative trait locus (QTL) for whole-blood serotonin levels in the Hutterites (P = 0.0003). Here, we demonstrate associations between variation in ITGB3 and serotonin levels in two outbred samples (P = 0.010 and 0.015). Lastly, we show that a coding variant of ITGB3 is associated with autism susceptibility in a large multiplex sample (P = 0.00082), and that this variation has different effects in males and females (P = 0.0018).
- Published
- 2006
- Full Text
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12. Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample.
- Author
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Weiss LA, Abney M, Parry R, Scanu AM, Cook EH Jr, and Ober C
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Blood Pressure, Child, Female, Founder Effect, Humans, Male, Middle Aged, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Protein Precursors, Quantitative Trait Loci, Sex Factors, South Dakota, Cardiovascular Diseases etiology, Cardiovascular Diseases genetics, Integrin beta3 genetics, Integrin beta3 physiology, Lipoproteins blood, Serotonin blood
- Abstract
A recent genome-scan identified the Leu33Pro polymorphism in the beta3 integrin (ITGB3) gene as a quantitative trait locus for whole blood serotonin level in a large Hutterite pedigree. Because both the Leu33Pro polymorphism and the serotonin system have been implicated in cardiovascular disease (CVD) risk and treatment response, we studied additional variation in ITGB3 and its relationship to intermediate phenotypes associated with CVD in the same population. We examined associations between 15 single nucleotide polymorphisms (SNPs) across ITGB3 and five CVD-related traits in the Hutterites: plasma levels of high density lipoprotein-cholesterol (HDL-c), triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), and lipoprotein(a) [Lp(a)] and blood pressure or hypertension. Seven of these SNPs in ITGB3 were associated with whole blood serotonin. Among the intermediate CVD-related phenotypes, only Lp(a) was associated with multiple ITGB3 SNPs, five of which were also associated with serotonin. A sex-stratified analysis revealed that the association between ITGB3 and Lp(a) is present only in females, whereas the association between ITGB3 and serotonin is concentrated in males. Our results suggest that variation in ITGB3 in addition to Leu33Pro could contribute to susceptibility to CVD and serotonin in a sex-specific manner.
- Published
- 2005
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13. Sex-specific genetic architecture of whole blood serotonin levels.
- Author
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Weiss LA, Abney M, Cook EH Jr, and Ober C
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Chromosome Mapping, Female, Founder Effect, Genetic Linkage, Humans, Male, Microsatellite Repeats, Middle Aged, Quantitative Trait, Heritable, Serotonin blood, Serotonin genetics, Sex Characteristics
- Abstract
Recently, a quantitative-trait locus (QTL) for whole blood serotonin level was identified in a genomewide linkage and association study in a founder population. Because serotonin level is a sexually dimorphic trait, in the present study, we evaluated the sex-specific genetic architecture of whole blood serotonin level in the same population. Here, we use an extended homozygosity-by-descent linkage method that is suitable for large complex pedigrees. Although both males and females have high broad heritability (H2=0.99), females have a higher additive component (h2=0.63 in females; h2=0.27 in males). Furthermore, the serotonin QTL on 17q that was identified previously in this population, integrin beta 3 (ITGB3), and a novel locus on 2q influence serotonin levels only in males, whereas linkage to a region on chromosome 6q is specific to females. Both sexes contribute to linkage signals on 12q and 16p. There were, overall, more associations meeting criteria for suggestive significance in males than in females, including those of ITGB3 and the serotonin transporter gene (5HTT). This analysis is consistent with heritable sexual dimorphism in whole blood serotonin levels resulting from the effects of a combination of sex-specific and sex-independent loci.
- Published
- 2005
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14. Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin.
- Author
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Weiss LA, Veenstra-Vanderweele J, Newman DL, Kim SJ, Dytch H, McPeek MS, Cheng S, Ober C, Cook EH Jr, and Abney M
- Subjects
- Female, Gene Frequency, Genetic Linkage, Humans, Lod Score, Male, Microsatellite Repeats, Pedigree, Integrin beta3 genetics, Quantitative Trait Loci, Serotonin blood
- Abstract
Serotonin has been implicated in common disorders involving the central nervous, gastrointestinal, cardiovascular, and pulmonary systems. We describe the first genome-wide screen to identify quantitative trait loci (QTLs) influencing whole blood serotonin in 567 members of a single large pedigree, using a novel association-based mapping approach. We identified an association between the beta3 integrin (ITGB3) Leu33Pro polymorphism on 17q21 and whole blood serotonin levels (P-value = 9.8 x 10(-5)). This variant explained the evidence for linkage in this region when included as a covariate in the linkage analysis (change in LOD from 1.87 to 0.16), indicating that ITGB3 may be an important serotonin QTL.
- Published
- 2004
- Full Text
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15. Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism.
- Author
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Stoltenberg SF, Twitchell GR, Hanna GL, Cook EH, Fitzgerald HE, Zucker RA, and Little KY
- Subjects
- Alcoholism blood, Alcoholism psychology, Alleles, DNA genetics, Family Health, Female, Gene Frequency, Genotype, Humans, Male, Personality Assessment, Polymorphism, Genetic, Psychiatric Status Rating Scales, Serotonin Plasma Membrane Transport Proteins, Alcoholism genetics, Carrier Proteins genetics, Membrane Glycoproteins genetics, Membrane Transport Proteins, Nerve Tissue Proteins, Personality genetics, Promoter Regions, Genetic genetics, Serotonin blood
- Abstract
A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) is considered to be a plausible candidate gene for anxiety-related personality traits and for alcoholism. Empirical support for the association between 5-HTTLPR and psychological traits has been somewhat inconsistent; however, observations of the functional dominance of the low-activity s-allele over the l-allele have been more consistent. When studying the influence of particular genes on psychological traits, it seems useful also to assess more biological intermediate traits that may mediate the effects of those genes on the traits of interest. The present study examined relationships between 5-HTTLPR genotype, whole blood serotonin (5-HT) level, and platelet 5-HT binding in 150 Caucasian subjects from 50 biological families. Individuals with the s-allele had lower average platelet 5-HT binding availability than those with the l/l genotype (P<0.025). Whole blood 5-HT level was not associated with 5-HTTLPR genotype. In adult men, those with the s-allele had higher mean scores on the NEO-FFI personality trait of openness than did those with the l/l genotype (P=0.002). The effect was not statistically significant in women (P=0.42), although it was in the same direction. Our findings do not support an association of 5-HTTLPR genotype with alcoholism diagnosis, alcoholism subtype, or the personality trait of neuroticism. The results of this pilot study suggest that further work should examine the mediation of the genetic effects on personality traits by biochemical measures and their moderation by gender., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
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- View/download PDF
16. Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration.
- Author
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Anderson, George M, Cook, Edwin H, Blakely, Randy D, Sutcliffe, James S, and Veenstra-VanderWeele, Jeremy
- Subjects
POST-acute COVID-19 syndrome ,SEROTONIN ,SEROTONIN uptake inhibitors ,BLOOD platelet aggregation ,SEROTONIN transporters - Abstract
We believe there are serious problems with a recently published and highly publicized paper entitled "Serotonin reduction in post-acute sequelae of viral infection." The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the "Discussion" section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, "Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment", it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs' effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
17. 1Is there sexual dimorphism of hyperserotonemia in Autism Spectrum Disorder?
- Author
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Shuffrey, Lauren C., Guter, Stephen J., Delaney, Shannon, Jacob, Suma, Anderson, George M., Sutcliffe, James S., Cook, Edwin H., and Veenstra-VanderWeele, Jeremy
- Subjects
Male ,Risk ,Serotonin ,Sex Characteristics ,Sex Factors ,Autism Spectrum Disorder ,mental disorders ,Humans ,Female ,Child ,behavioral disciplines and activities ,Article ,Biomarkers - Abstract
Approximately 30% of individuals with autism spectrum disorder (ASD) have elevated whole blood serotonin (5-HT) levels. Genetic linkage and association studies of ASD and of whole blood 5-HT levels as a quantitative trait have revealed sexual dimorphism. Few studies have examined the presence of a sex difference on hyperserotonemia within ASD. To assess whether the rate of hyperserotonemia is different in males than in females with ASD, we measured whole blood 5-HT levels in 292 children and adolescents with ASD, the largest sample in which this biomarker has been assessed. Based upon previous work suggesting that hyperserotonemia is more common prior to puberty, we focused our analysis on the 182 pre-pubertal children with ASD. 42% of pre-pubertal participants were within the hyperserotonemia range. In this population, we found that males were significantly more likely to manifest hyperserotonemia than females (P = 0.03). As expected, no significant difference was found in the post-pubertal population. Additional work will be needed to replicate this intriguing finding and to understand whether it could potentially explain differences in patterns of ASD risk between males and females. Autism Res 2017, 10: 1417-1423. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
- Published
- 2017
18. Is there sexual dimorphism of hyperserotonemia in autism spectrum disorder?
- Author
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Shuffrey, Lauren C., Guter, Stephen J., Delaney, Shannon, Jacob, Suma, Anderson, George M., Sutcliffe, James S., Cook, Edwin H., and Veenstra‐VanderWeele, Jeremy
- Abstract
Approximately 30% of individuals with autism spectrum disorder (ASD) have elevated whole blood serotonin (5-HT) levels. Genetic linkage and association studies of ASD and of whole blood 5-HT levels as a quantitative trait have revealed sexual dimorphism. Few studies have examined the presence of a sex difference on hyperserotonemia within ASD. To assess whether the rate of hyperserotonemia is different in males than in females with ASD, we measured whole blood 5-HT levels in 292 children and adolescents with ASD, the largest sample in which this biomarker has been assessed. Based upon previous work suggesting that hyperserotonemia is more common prior to puberty, we focused our analysis on the 182 pre-pubertal children with ASD. 42% of pre-pubertal participants were within the hyperserotonemia range. In this population, we found that males were significantly more likely to manifest hyperserotonemia than females ( P = 0.03). As expected, no significant difference was found in the post-pubertal population. Additional work will be needed to replicate this intriguing finding and to understand whether it could potentially explain differences in patterns of ASD risk between males and females. Autism Res 2017, 10: 1417-1423. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
19. Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.
- Author
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Rui Chen, Davis, Lea K., Guter, Stephen, Qiang Wei, Jacob, Suma, Potter, Melissa H., Cox, Nancy J., Cook, Edwin H., Sutcliffe, James S., and Li, Bingshan
- Subjects
SEROTONIN ,AUTISM spectrum disorders - Abstract
Background: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. Methods: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. Results: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. Conclusions: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
20. Parental Broader Autism Subphenotypes in ASD Affected Families: Relationship to Gender, Child's Symptoms, SSRI Treatment, and Platelet Serotonin.
- Author
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Levin‐Decanini, Tal, Maltman, Nell, Francis, Sunday M., Guter, Steve, Anderson, George M., Cook, Edwin H., and Jacob, Suma
- Abstract
Relationships between parental broader autism phenotype ( BAP) scores, gender, selective serotonin reuptake inhibitor ( SSRI) treatment, serotonin (5 HT) levels, and the child's symptoms were investigated in a family study of autism spectrum disorder ( ASD). The Broader Autism Phenotype Questionnaire ( BAPQ) was used to measure the BAP of 275 parents. Fathers not taking SSRIs ( F- SSRI; n = 115) scored significantly higher on BAP Total and Aloof subscales compared to mothers not receiving treatment ( M- SSRI; n = 136.) However, mothers taking SSRIs ( M + SSRI; n = 19) scored higher than those not taking medication on BAP Total and Rigid subscales, and they were more likely to be BAPQ Total, Aloof, and Rigid positive. Significant correlations were noted between proband autism symptoms and parental BAPQ scores such that Total, Aloof, and Rigid subscale scores of F- SSRI correlated with proband restricted repetitive behavior ( RRB) measures on the ADOS, CRI, and RBS-R. However, only the Aloof subscale score of M + SSRI correlated with proband RRB on the ADOS. The correlation between the BAPQ scores of mothers taking SSRIs and child scores, as well as the increase in BAPQ scores of this group of mothers, requires careful interpretation and further study because correlations would not withstand multiple corrections. As expected by previous research, significant parent-child correlations were observed for 5 HT levels. However, 5 HT levels were not correlated with behavioral measures. Study results suggest that the expression of the BAP varies not only across parental gender, but also across individuals using psychotropic medication and those who do not. Autism Res 2013, 6: 621-630. © 2013 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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21. 5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism.
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Brune, Camille W., Soo-Jeong Kim, Salt, Jeff, Leventhal, Bennett L., Lord, Catherine, and Cook, Edwin H.
- Subjects
GENOTYPE-environment interaction ,PHENOTYPES ,AUTISM in children ,SEROTONIN ,NEUROTRANSMITTERS ,GENETIC polymorphisms - Abstract
Objective: The serotonin transporter gene (SLC6A4) is a strong autism candidate gene because of its association with anxiety, aggression and attention, and the effectiveness of selective serotonin re-uptake inhibitors (SSRIs) in treating certain behavioral symptoms. In families with individuals with autism, several reports of biased transmission of both alleles (short, long) at the serotonin transporter gene promotor polymorphism (5-HTTLPR) locus of SLC6A4 now exist. The heterogeneity in these reports may be due to clinical heterogeneity. The authors hypothesized that 5-HTTLPR genotypes would be related to variation in specific symptoms in children with autism. Method: The authors explored whether variants of two functional polymorphisms of SLC6A4 (5-HTTLPR, intron 2 variable number tandem repeat [2 VNTR]) were related to behavioral characteristics measured by the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Subjects (N=73, age 3–19 years old) met diagnostic criteria for autistic disorder based on both measures. Results: Evidence of genotype-phenotype interactions on the Autism Diagnostic Interview-Revised was found with the 5-HTTLPR short group of HTTLPR (S/L or S/S genotypes) being rated as more severe on the subdomain ‘failure to use nonverbal communication to regulate social interaction,’ and the long group (L/L genotype) being more severe on the sub-domain ‘stereotyped and repetitive motor mannerisms’ and on an aggression measure. In contrast, on the Autism Diagnostic Observation Schedule, the long group was associated with greater severity on directed facial expressions and unusual sensory interests. There were no significant relationships between the intron 2 VNTR genotypes and subdomains or domains of symptoms on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. Conclusions: These findings provide initial support for genotype-specific phenotypes for 5-HTTLPR in autism based on ratings from the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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22. Serotonin transporter genotype and acute subjective response to amphetamine.
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Lott, David C., Kim, Soo‐Jeong, Cook, Edwin H., and Wit, Harriet.
- Subjects
SEROTONIN ,DOPAMINE ,GENOTYPE-environment interaction ,AMPHETAMINES ,AMPHETAMINE abuse ,GENETIC polymorphisms ,SUBSTANCE abuse & psychology ,AFFECT (Psychology) ,ALLELES ,AROUSAL (Physiology) ,COMPARATIVE studies ,CROSSOVER trials ,DOSE-effect relationship in pharmacology ,GENES ,GENOMES ,RESEARCH methodology ,MEDICAL cooperation ,MEMBRANE proteins ,POLYMERASE chain reaction ,RESEARCH ,SUBSTANCE abuse ,EVALUATION research ,RANDOMIZED controlled trials ,BLIND experiment ,DEXTROAMPHETAMINE ,GENOTYPES ,PHARMACODYNAMICS - Abstract
The authors have previously shown an effect of dopamine transporter genotype on acute subjective responses to d-amphetamine, which may affect risk of addiction. They now report the results of an evaluation of the role of the serotonin transporter gene (HTT) using a double-blind, placebo-controlled, crossover design in which subjects (N = 101) completed self-report measures of subjective effect. The separate and combined analyses of the gene-linked polymorphic region (5-HTTLPR) and the Intron 2 VNTR suggest that these two HTT polymorphisms may contribute to acute subjective responses to d-amphetamine with a small effect. [ABSTRACT FROM AUTHOR]
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- 2006
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23. Sertraline in Children and Adolescents With Obsessive-Compulsive Disorder.
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March, John S., Biederman, Joseph, Wolkow, Robert, Safferman, Allan, Mardekian, Jack, Cook, Edwin H., Cutler, Neal R., Dominguez, Roberto, Ferguson, James, Muller, Betty, Riesenberg, Robert, Rosenthal, Murray, Sallee, Floyd R., Steiner, Hans, and Wagner, Karen D.
- Subjects
OBSESSIVE-compulsive disorder in children ,OBSESSIVE-compulsive disorder in adolescence ,SEROTONIN ,PSYCHOPHARMACOLOGY ,CLINICAL trials ,THERAPEUTICS - Abstract
Presents a study to evaluate the safety and efficacy of the selective serotonin reuptake inhibitor sertraline hydrochloride in children and adolescents with obsessive-compulsive disorder. Design; Patients; Setting; Intervention; Main outcome measures; Results; Conclusion.
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- 1998
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24. Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and...
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Little, Karley Y., McLaughlin, Daniel P., Zhang, Lian, Livermore, Cynthia S., Dalack, Gregory W., McFinton, Patrick R., DelProposto, Zachery S., Hill, Elizabeth, Cassin, Bader J., Watson, Stanley J., and Cook, Edwin H.
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SEROTONIN - Abstract
Examines a hypothesis, which alterations in brain serotonin transporter function exists in chronic users of ethanol and cocaine. Information on platelet and postmortem brain studies; Performance of quantitative autoradiographic and in situ hybridization assays; Conclusions of the study.
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- 1998
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25. Maternal depressive history, teen 5HTTLPR genotype, and the processing of emotional faces: Exploring mechanisms of risk
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Jacobs, Rachel H., Pine, Daniel S., Schoeny, Michael E., Henry, David B., Gollan, Jackie K., Moy, Gregory, Cook, Edwin H., and Wakschlag, Lauren S.
- Subjects
- *
MATERNAL deprivation , *SEROTONIN , *ANXIETY , *FACIAL expression , *MENTAL depression risk factors , *MENTAL health , *INDIVIDUAL differences , *DEPRESSION in women , *HUMAN information processing , *GENETICS - Abstract
Abstract: Variations in the serotonin transporter gene (5HTTLPR) and biased processing of face-emotion displays both have been implicated in the transmission of depression risk, but little is known about developmental influences on these relationships. Within a community sample of adolescents, we examine whether 5HTTLPR genotype moderates the link between maternal depressive history and errors in face-emotion labeling. When controlling for current levels of depression and anxiety among youth, a two-way interaction between maternal depressive history and 5HTTLPR genotype was detected. Specifically, adolescents whose mothers reported a depressive history and who had a low expressing genotype made more errors in classifying emotional faces when compared with adolescents with an intermediate or high expressing genotype, with or without maternal depression history. These findings highlight the complex manner in which maternal depression and genetic risk may interact to predict individual differences in social information processing. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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26. 4.12 Maternal Whole Blood Serotonin Levels Predict Verbal Ability and Core Symptoms in Children With Autism Spectrum Disorder.
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Montgomery, Alicia K., Shuffrey, Lauren C., Guter, Stephen J., Anderson, George M., Jacob, Suma, Sutcliffe, James S., Turner, J. Blake, Cook, Edwin H., and Veenstra-VanderWeele, Jeremy
- Subjects
- *
CHILDREN with autism spectrum disorders , *VERBAL ability , *SEROTONIN - Published
- 2017
- Full Text
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