Biomedical subjects

Edwin H Cook

Publications and source records attributed to Edwin H Cook.

At least 19 recordsLinked to original sources

PubMed2007

Association of dopamine transporter genotype with disruptive behavior disorders in an eight-year longitudinal study of children and adolescents.

Associations between dopamine transporter (DAT1) variable number tandem repeats (VNTR), genotypes, and disruptive behavior were examined in an 8-year longitudinal study of children (n = 183). Half of the children met criteria for attention-deficit/hyperactivity disorder (ADHD) at 4-6 years and half were non-referred comparison children. Consistent with several studies, the non-additive association for the 10-repeat allele was significant for hyperactivity-impulsivity (HI) symptoms. However, consistent with other studies, exploratory analyses of the non-additive association of the 9-repeat allele of DAT1 with HI and oppositional defiant disorder (ODD) symptoms also were significant. The inconsistent association between DAT1 and child behavior problems in this and other samples may reflect joint influence of the 10-repeat and 9-repeat alleles.

Adolescent↗

PubMed2006

High frequency of neurexin 1beta signal peptide structural variants in patients with autism.

Neuroligins are postsynaptic membrane cell-adhesion molecules which bind to beta-neurexins, a family of proteins that act as neuronal cell surface receptors. To explore the possibility that structural variants in the beta-neurexin genes predispose to autism, the coding regions and associated splice junctions of three beta-neurexin genes were scanned with detection of virtually all mutations-SSCP (DOVAM-S) in 72 Caucasian patients with autism. In addition, segments of the neurexin 1beta gene were sequenced in 131 additional Caucasian and 61 Afro-American patients with autism from South Carolina and the Midwest. Two putative missense structural variants were identified in the neurexin 1beta gene in four Caucasian patients with autism and not in 535 healthy Caucasian controls (4/203 vs. 0/535, P=0.0056). Initial family data suggest that incomplete penetrance may occur. In addition, no structural variant was found in the neurexin 2beta gene and the neurexin 3beta gene. In the context of all available data, we conclude that mutations of the neurexin 1beta gene may contribute to autism susceptibility.

Abnormalities, Multiple↗

PubMed2006

An association study of the brain-derived neurotrophic factor Val66Met polymorphism and amphetamine response.

Although genetic factors are known to be important in addiction, no candidate genes have yet been consistently linked to drug use or abuse. Brain-derived neurotrophic factor (BDNF), which has been implicated in the behavioral response to psychomotor stimulants and potentiates neurotransmitters that are strongly linked to addiction, is a logical candidate gene to study. Using a drug challenge approach, we tested for association between BDNF G196A (val66met) genotype and subjective responses to amphetamine (AMPH). Healthy volunteers participated in a double blind, crossover design in which they received placebo, 10 mg, and 20 mg oral d-amphetamine in random order. Subjective and physical responses to ingestion of AMPH were measured at 30-min intervals after drug ingestion. Each subject was genotyped for the BDNF G196A polymorphism and grouped and analyzed accordingly. The effects of AMPH on ratings of arousal, energy, and heart rate were compared in subjects with the val/val genotype (N = 67) and the subjects with either the val/met or met/met genotypes (N = 32). AMPH produced less pronounced self-ratings of arousal and energy, yet higher increases in heart rate, in the val/met and met/met compared to the val/val group. These results suggest that BDNF is related to the subjective and physical response to low doses of AMPH.

Adult↗

PubMed2006

ITGB3 shows genetic and expression interaction with SLC6A4.

Autism affects more males than females and is associated with disturbances of the serotonin system. The integrin beta3 (ITGB3) and serotonin transporter (SLC6A4) genes were both recently identified as male quantitative trait loci (QTLs) for serotonin levels and alleles of each have been associated with autism. Here, we use publicly available genomic resources to determine whether regulation of expression level could be the mechanism behind association between serotonin level and noncoding variation in ITGB3. We also examine whether ITGB3 might interact with SLC6A4 to contribute to autism susceptibility. Using murine and human expression data, we observe that ITGB3 and SLC6A4 expression levels are correlated (0.38<r<0.78). Moreover, genetic variation in ITGB3 is associated with expression of both ITGB3 (P=0.012) and SLC6A4 (P=0.008) in unrelated CEPH individuals. We also show preliminary evidence that genotypes at the ITGB3 and SLC6A4 loci may interact to affect autism susceptibility (P=0.033).

Animals↗

PubMed2006

Variation in ITGB3 is associated with whole-blood serotonin level and autism susceptibility.

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).

Alleles↗

PubMed2006

New complexities in the genetics of stuttering: significant sex-specific linkage signals.

Stuttering is a speech disorder long recognized to have a genetic component. Recent linkage studies mapped a susceptibility locus for stuttering to chromosome 12 in 46 highly inbred families ascertained in Pakistan. We report here on linkage studies in 100 families of European descent ascertained in the United States, Sweden, and Israel. These families included 252 individuals exhibiting persistent stuttering, 45 individuals classified as recovered from stuttering, and 19 individuals too young to classify. Primary analyses identified moderate evidence for linkage of the broader diagnosis of "ever stuttered" (including both persistent and recovered stuttering) on chromosome 9 (LOD = 2.3 at 60 cM) and of the narrower diagnosis of persistent stuttering on chromosome 15 (LOD = 1.95 at 23 cM). In contrast, sex-specific evidence for linkage on chromosome 7 at 153 cM in the male-only data subset (LOD = 2.99) and on chromosome 21 at 34 cM in the female-only data subset (LOD = 4.5) met genomewide criteria for significance. Secondary analyses revealed a significant increase in the evidence for linkage on chromosome 12, conditional on the evidence for linkage at chromosome 7, with the location of the increased signal congruent with the previously reported signal in families ascertained in Pakistan. In addition, a region on chromosome 2 (193 cM) showed a significant increase in the evidence for linkage conditional on either chromosome 9 (positive) or chromosome 7 (negative); this chromosome 2 region has been implicated elsewhere in studies on autism, with increased evidence for linkage observed when the sample is restricted to those with delayed onset of phrase speech. Our results support the hypothesis that the genetic component to stuttering has significant sex effects.

Chromosome Mapping↗

PubMed2006

Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder.

CONTEXT: The first 2 independent linkage studies for obsessive-compulsive disorder (OCD) identified a region on 9p24 with suggestive evidence for linkage. The glutamate transporter gene solute carrier family 1, member 1 (SLC1A1) is a promising functional candidate in this region because altered glutamatergic concentrations have been found in the striatum and anterior cingulate in neuroimaging studies of pediatric OCD. OBJECTIVE: To determine whether genotypes at polymorphisms in the SLC1A1 gene region are associated with early-onset OCD. DESIGN: Family-based analysis of association using the transmission disequilibrium test, confirmed using the family-based association test. SETTING: Anxiety disorders program in an academic medical center. PARTICIPANTS: Seventy-one probands with DSM-III-R or DSM-IV OCD and their parents. METHODS: Nine single nucleotide polymorphisms spaced throughout the SLC1A1 gene region were genotyped. RESULTS: Significant association was detected at rs3780412 (P = .04) and rs301430 (P = .03), 2 common adjacent single nucleotide polymorphisms in the 3' region of SLC1A1. Analysis by sex revealed that association at rs3780412 was limited to male probands (P = .002). Significant association was also detected for the T/C haplotype at rs301430-rs301979 (P = .03), the only haplotype block identified among the 9 single nucleotide polymorphisms. Analysis by sex also revealed that the haplotype association was limited to male probands (P = .003). A deletion in the 3' flanking region of SLC1A1 was also detected that imperfectly segregated with OCD in a large, multigenerational family with multiple affected individuals. CONCLUSIONS: The 3' region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.

Adolescent↗

PubMed2006

Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine.

Animal models suggest that the casein kinase 1 epsilon gene (Csnk1e) contributes to variability in stimulant response. Csnk1e is a key component in the Darpp-32 (Dopamine-And-cAMP-Regulated-Phosphoprotein-32 kDa) second messenger pathway and has been implicated in previous pharmacological and pharmacogenetic studies in mice. Mice bred for methamphetamine sensitivity showed linkage to the region of chromosome 15 that contains Csnk1e and also showed a 10-fold increase in expression of Csnk1e. We used a double-blind, crossover design in healthy human volunteers to test association between polymorphisms in the CSNK1E region and subjective response to placebo, 10, or 20 mg of oral D-amphetamine. Repeated-measures ANOVA was used to analyze interactions between genotype and drug response. The primary outcome measure, subjects' ratings of whether they felt a drug effect (Drug Effects Questionnaire (DEQ)), revealed a significant effect (p=0.010) at one single-nucleotide polymorphism (rs135745). Subjects with more copies of the rs135745 C allele were more sensitive to the low dose of D-amphetamine (p=0.001), which corresponded to a leftward shift in the dose-response curve. These findings demonstrate the successful translation of pharmacogenetic results from mice to humans.

Adolescent↗

PubMed2006

A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders.

BACKGROUND: This pilot study examined the effectiveness of memantine hydrochloride in improving cognitive functioning and behavioral symptoms in children with pervasive developmental disorders (PDDs). METHOD: Subjects aged 3-12 years inclusive were enrolled in this 8-week, open-label study. Expressive and receptive language, nonverbal IQ, and nonverbal memory measures were administered at baseline and after 8 weeks of treatment with 0.4 mg/kg of memantine hydrochloride. Throughout the study, the Aberrant Behavior Checklist (ABC) was sent in weekly by parents as a measure of behavioral change. RESULTS: Twelve of 14 subjects completed the study. Significant improvement from baseline was noted on the memory test (Children's Memory Scale Dot Learning Subtest). There were no significant differences from baseline on measures of expressive or receptive language or nonverbal IQ. There were significant improvements on a number of ABC subscales, including hyperactivity, lethargy, and irritability. There were no overall significant statistical differences from baseline on the Clinical Global Improvement-Severity (CGI-S) scale. On the Clinical Global Improvement-Improvement (CGI-I), 4 of 14 subjects showed minimal improvement, and none was deemed "much-improved" or "very much improved." CONCLUSIONS: This small, prospective, open-label study suggests that memantine may be useful in the treatment of memory functioning and some behavioral symptoms in PDDs. The investigators did not see the same degree of change as endorsed by caretakers. Controlled studies are needed to substantiate and clarify these preliminary findings.

Child↗

PubMed2006

Combining information from multiple sources in the diagnosis of autism spectrum disorders.

BACKGROUND: Standard case criteria are proposed for combined use of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule to diagnose autism and to define the broader category of autism spectrum disorders. METHOD: Single and combined Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule algorithms were compared to best estimate diagnoses in four samples: U.S. (n = 960) and Canadian (n = 232) participants 3 years and older, U.S. participants younger than 36 months (n = 270), and U.S. participants older than 36 months with profound mental retardation (n = 67). RESULTS: Sensitivities and specificities of 80% and higher were obtained when strict criteria for an autism diagnosis using both instruments were applied in the U.S. samples, and 75% or greater in the Canadian sample. Single-instrument criteria resulted in significant loss of specificity. Specificity was poor in the sample with profound mental retardation. Lower sensitivity and specificity were also obtained when proposed criteria for broader spectrum disorders were applied. CONCLUSIONS: The Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule make independent, additive contributions to the judgment of clinicians that result in a more consistent and rigorous application of diagnostic criteria.

Asperger Syndrome↗

PubMed2006

5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism.

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 reuptake 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 subdomain "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.

Adolescent↗

PubMed2005

Interindividual variation in anxiety response to amphetamine: possible role for adenosine A2A receptor gene variants.

Amphetamine is thought to produce its stimulant effects mainly via the dopamine system, but its effects may also be influenced by other systems. Dopamine D1 and D2 receptors exist as heterodimers with adenosine A1 and A(2A) receptors, which modulate their responsiveness, suggesting that responses to amphetamine may also depend on adenosinergic function. We therefore studied the relevance of one adenosine A1 and three adenosine A(2A) receptor gene polymorphisms for the interindividual variability in amphetamine response in 99 healthy volunteers who received placebo or d-amphetamine (10 or 20 mg). The 1976C/T and 2592C/T(ins) polymorphisms of the adenosine receptor gene were associated with increases in anxiety at both doses. This is consistent with recent observations indicating a role for adenosine A(2A) receptor gene polymorphisms in anxiety.

Adolescent↗

PubMed2005

Family-based association study of DAT1 and DRD4 polymorphism in Korean children with ADHD.

Although the etiology of Attention Deficit/Hyperactivity Disorder (ADHD) is not well understood, evidence from the family and twin studies suggest that ADHD is familial and highly heritable. The aim of the study was to test whether dopamine transporter gene (DAT1) and dopamine receptor D4 gene (DRD4) polymorphisms are in linkage disequilibrium with ADHD in Korean children, using a family-based association study. One hundred and twenty-six trios were studied and 87% of probands were boys (mean age=8.2 years, mean IQ=104). ADHD not otherwise specified (NOS) was the most common subtype and comorbidity rates were low. Descriptive analysis and the TDT test were the primary analyses. In exploratory analyses, logistic regression and QTDT were performed. The 10-repeat allele and 4-repeat allele were the most frequent for DAT1 and DRD4. TDT test for DAT1 and DRD4 did not show preferential transmission. Based on logistic regression and QTDT, the 5-repeat allele of DRD4 may confer protection for hyperactive-impulsivity symptom severity compared to the 4-repeat allele. The negative TDT finding between DAT1 and DRD4 VNTR polymorphisms and ADHD should be interpreted with caution; partly due to lack of power caused by low heterozygosity in the study population. Future studies are necessary to test the hypothesis generated in this study that the 5-repeat allele of DRD4 is protective for hyperactive-impulsivity symptom severity compared to the 4-repeat allele.

Analysis of Variance↗

PubMed2005

Global gene expression as a function of germline genetic variation.

Common, functional, germline genetic polymorphisms have been associated with clinical cancer outcomes. Little attention has been paid to the potential phenotypic consequences of germline genetic variation on downstream genes. We determined the germline status of 16 well-characterized functional polymorphisms in 126 children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression profiles of diagnostic ALL blasts from the same patients differed by these germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*28) and GSTM1 deletion were significant predictors of global gene expression in a supervised approach, which divided patients based on their germline genotypes [UGT1A1: 124 probe sets, false discovery rate (FDR)=13%, P< or =0.0031; GSTM1: 112 probe sets, FDR=42.5%, P< or =0.0084]. Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those that distinguished the GSTM1 null genotype from non-null genotype included NBS1 and PRKR. In an unsupervised approach, the gene expression profiles using the entire array delineated two major clusters of patients. The only germline genotype frequency that differed between the two clusters was UGT1A1 (P=0.002; Fisher's exact test). Although their expression is limited to specific tissues, both GSTM1 and UGT1A1 are involved in the conjugation (and thus transport, excretion and lipophilicity) of a broad range of endobiotics and xenobiotics, which could plausibly have consequences for gene expression in different tissues.

Child↗

PubMed2005

Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample.

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.

Adolescent↗

PubMed2005

Pharmacogenetics of outcome in children with acute lymphoblastic leukemia.

Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) non-null genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy.

Alleles↗

PubMed2005

Structural variants in the retinoid receptor genes in patients with schizophrenia and other psychiatric diseases.

Retinoid receptors (RARs and RXRs) regulate brain morphogenesis and function. Defects in these receptors may contribute to schizophrenia or other psychiatric diseases. To test the hypothesis that genetic variants of the retinoid receptor genes may predispose to schizophrenia and other psychiatric diseases, the six RAR and RXR genes and a heterodimer partner, the NURR1 gene, were scanned in 100 schizophrenia patients, along with pilot studies in 20-24 patients with bipolar disorder (BPD), attention-deficit hyperactivity disorder (ADHD), autism, or alcoholism. A total of 5.4 megabases of genomic sequence was scanned. No variants affecting protein structure or expression (VAPSEs) were found in four of the genes. One uncommon missense variant was found in each of the RARbeta, RARgamma, and RXRgamma genes. We conclude that structural variants in the RAR/RXR and NURR1 genes do not play a major role in the etiology of schizophrenia.

Alcoholism↗

PubMed2005

Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases.

Intriguing parallels have been noted previously between the biology of Vitamin D and the epidemiology of schizophrenia. We have scanned the Vitamin D receptor (VDR) gene by DOVAM-S (Detection of Virtually All Mutations-SSCP), a robotically enhanced multiplexed scanning method. In total, 100 patients with schizophrenia (86 Caucasians and 14 African-Americans) were scanned. In addition, pilot experiments were performed in patients with bipolar disorder (BPD) (24), autism (24), attention deficit hyperactivity disorder (ADHD) (24), and alcoholism (20). A total of 762 kb of the VDR genomic sequence was scanned. R208N and V339I were each found in one African-American patient, while absent in 35 African-American controls without schizophrenia (2/14 versus 0/35, P=0.08). Within the power of the study (> or =1.6-fold relative risk), the common M1T variant is not associated with schizophrenia. In the 92 scanned patients with other psychiatric diseases, R173S was found in a single patient with bipolar disorder. In conclusion, we describe three novel structural variants of the Vitamin D receptor. Further study is required to clarify their role, if any, in psychiatric disease.

Amino Acid Sequence↗