Biomedical subjects

J L Kennedy

Publications and source records attributed to J L Kennedy.

At least 19 recordsLinked to original sources

PubMed2006

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

Adult↗

PubMed2006

Association study of the adrenergic receptors and childhood-onset mood disorders in Hungarian families.

The adrenergic system has been implicated in the etiology of depression based on a number of lines of evidence, particularly, the mechanism of some classes of antidepressants which increase the synaptic levels of norepinephrine. Further, several genome scans for mood disorders, both unipolar and bipolar, have indicated linkage to the chromosomal regions of 5q23-q33.3, 8p12-p11.2, 4p16, and 10q24-q26, the location of the adrenergic receptors alpha1B (ADRA1B), beta3 (ADRB3), alpha2C (ADRA2C), alpha2A (ADRA2A), and beta1 (ADRB1). In this manuscript, we report on the relationship of the adrenergic receptors and depression using a family based association approach and 189 families (223 affected children) with childhood-onset mood disorder (COMD) collected in Hungary. We found no significant evidence for an association with any of the 24 markers, in total, tested across these genes using single marker analysis or haplotypes of markers across these genes. The results in the present sample indicate that these nine genes are unlikely to be major susceptibility genes contributing to COMD.

Adolescent↗

PubMed2006

Regulation of alpha7-nicotinic receptor subunit and alpha7-like gene expression in the prefrontal cortex of patients with bipolar disorder and schizophrenia.

OBJECTIVE: The alpha7-nicotinic receptor subunit gene (CHRNA7) is located at chromosome 15q13-14, a region previously linked with schizophrenia. Genetic association and mRNA expression studies also implicate CHRNA7 in schizophrenia. The CHRNA7 gene has a partial duplication that constitutes the alpha7-like nicotinic receptor gene (CHRFAM7A). We hypothesized that major psychoses could affect the expression of both CHRNA7 and CHRFAM7A. METHOD: CHRNA7 and CHRFAM7A mRNA levels were measured in postmortem prefrontal cortex (donated by the Stanley Foundation) from subjects with schizophrenia, bipolar disorder and unaffected controls (n = 35 each). RESULTS: The mRNA levels of alpha7 and alpha7-like genes have a positive correlation overall (r = 0.25; P = 0.009), however, there is no significant difference in the expression of CHRNA7 among the three diagnostic groups. CONCLUSION: This correlation is driven by the bipolar group (r = 0.43; P = 0.009), and is absent in schizophrenia and unaffected controls, suggesting an alteration in the CHRNA7:CHRFAM7A ratio in bipolar disorder.

Adult↗

PubMed2006

The interaction between TPH2 promoter haplotypes and clinical-demographic risk factors in suicide victims with major psychoses.

Tryptophan hydroxylase isoform 2 (TPH2) is a rate-limiting enzyme in the biosynthesis of serotonin (5-HT) and is predominantly localized in the brain. Previous studies have suggested that there is an association between serotonergic dysfunction in the brain and suicidality. This study was designed to examine whether the -473T > A and -8396G > C polymorphisms of the TPH2 gene may be associated with completed suicide in subjects with major psychoses from the Stanley Foundation Brain Bank sample. TPH2 genotypes were determined in 69 subjects with a diagnosis of schizophrenia or bipolar disorder, among which 22 died by suicide. Genomic DNA was amplified by polymerase chain reaction and typed by automated methods. Both markers were found to be in Hardy-Weinberg equilibrium and in strong linkage disequilibrium. No association with history of suicide was found for either polymorphism. Haplotype analysis with EHAP showed no association between completed suicide and haplotype distribution (chi2 = 1.877; 3 df; P = 0.598). Nor was there any association between suicide and these genetic markers even when clinical-demographic factors were considered as covariates in the haplotype analysis. These findings suggest that these 5' marker haplotypes in the TPH2 gene do not influence suicidal behaviour.

Adult↗

PubMed2005

Association study of CREB1 and childhood-onset mood disorders.

Several lines of evidence suggest that the cellular pathways involved in synaptic plasticity contribute to the risk of depression. These findings include the evidence that chronic antidepressant treatment upregulates the cAMP signal transduction cascade resulting in increased expression and function of the cAMP responsive element binding protein (CREB), a transcription factor that increases the expression of key growth factors involved in synaptogenesis and neurogenesis. Recently, linkage to CREB1 was reported for early-onset depression in families recruited from the Pittsburgh area. This finding was significant only in female sibling pairs from those families. Two specific DNA variants, -656G/A and a C insertion/deletion in intron 8, were identified in CREB1 that co-segregated with depression in two of the families. We sought to investigate the relationship of CREB1 to childhood-onset mood disorders (COMD) using a sample of 195 nuclear families (225 affected children) collected in Hungary. We genotyped the two CREB1 DNA variants previously identified as linked to depression as well as three additional polymorphisms spanning the gene. In addition, we genotyped the -656G/A DNA change and the intron 8 polymorphism in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matched controls, and examined the distribution of alleles. The -656A allele was not observed in our samples and there was no evidence for association of the intron 8 polymorphism in either the sample from Pittsburgh (chi(2) = 0.061, 1 d.f., P = 0.803) or Hungary (chi(2) = 0.040, 1 d.f., P = 0.842). We found no evidence for an association with the other three polymorphisms or with the haplotypes of these markers. Further, we found no sex-specific relationship. Our results, therefore, do not support the previous evidence for this gene as a major factor contributing to depression.

Adolescent↗

PubMed2005

The serotonin-1Dbeta receptor gene and severity of obsessive-compulsive disorder in women with bulimia nervosa.

BACKGROUND: There is significant evidence that eating disorders have an important biological overlap with obsessive-compulsive disorder (OCD), though the specific mediators of this relationship remain unclear. Recent evidence suggests that the G861C polymorphism of the 5HT-1Dbeta receptor gene and the G allele in particular may play a role in OCD. We thus hypothesized that, among a heterogenous group of probands with bulimia nervosa (BN), this same G allele might predict the presence and/or severity of OCD pathology. METHODS: 165 consecutive female probands with BN were genotyped for the G861C polymorphism of the 5HT-1Dbeta receptor gene. Rates of full syndrome OCD, partial syndrome OCD and no OCD were compared across the three genotypic groups defined by this polymorphism. RESULTS: 45 out of 165 BN probands (27.3%) had either full or partial syndrome OCD. In the full sample, there was a significant difference in the distribution of the three diagnostic groups by genotype (chi2=10.07, df=4, p=.039). The G861C polymorphism did not strongly predict which probands had any vs. no OCD pathology. However, among the 45 probands with OCD symptoms, the G861C polymorphism did strongly differentiate full syndrome vs. partial syndrome OCD (chi2=9.26, df=2, p=.01; odds ratio for full syndrome OCD with GG genotype=7.69, 95% CI=1.45-40.9). DISCUSSION: In women with BN, the G861C polymorphism of the 5HT-1Dbeta gene does not appear to be associated with the generation of OCD symptoms; however, it might directly or indirectly be associated with a modulatory effect on syndrome severity in probands otherwise predisposed to OCD. While preliminary and in need of replication in other samples, this is the first association study to suggest how a particular gene might influence OCD pathology in an eating disorder population.

Adolescent↗

PubMed2005

Untranslated region haplotype in dysbindin gene: analysis in schizophrenia.

Genome-scans performed in schizophrenia families have provided evidence for region 6p24-21 where variability may confer susceptibility to schizophrenia. Recent studies have implicated that gene DTNBP1 (dysbindin) in this region is strongly associated with schizophrenia. In a family based association study we investigated three markers located in the untranslated region of the DTNBP1 gene: rs909706, rs1047631 and rs742106. The sample size of our study is 117 families. No biased transmission towards the disorder was detected by haplotype analysis using TRANSMIT.

Carrier Proteins↗

PubMed2005

Lack of association between polymorphism of the human cyclic GMP-dependent protein kinase gene and obesity.

OBJECTIVE: To investigate whether genetic variation in the cyclic GMP-dependent protein kinase gene (PRKG1) is associated with obesity. METHODS: The study included 143 individuals from New York City area, NY, USA. The subjects were sampled on the basis of body mass index (BMI): obese (BMI ranging from 33.8 to 89.5 kg/m(2)), and nonobese (BMI ranging from 16.0 to 29.4 kg/m(2)). The association between C2276T polymorphism in PRKG1 gene and obesity was tested using linear regression analysis. RESULTS: BMI levels were predicted by linear regression models adjusted for demographic factors. An analysis was performed twice: in individuals of all ethnic backgrounds and in European-Americans only. In both cases, genotype did not have a significant effect. CONCLUSION: We found no evidence that the C2276T polymorphism in the PKRG1 gene is associated with obesity.

Adolescent↗

PubMed2005

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (chi2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.

Adult↗

PubMed2005

The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder.

The synaptosomal-associated protein of 25 kDa gene (SNAP25) has been suggested as a genetic susceptibility factor in attention-deficit hyperactivity disorder (ADHD) based on the mouse strain coloboma. This strain is hemizygous for the SNAP25 gene and displays hyperactivity that responds to dextroamphetamine, but not to methylphenidate. Previously, we reported association of SNAP25 and ADHD using two polymorphisms. To further investigate this gene, we screened the exons for DNA variation and genotyped ten additional polymorphisms in an expanded sample of families from Toronto and a second sample of families collected in Irvine, CA. Significant results were observed in the Toronto sample for four markers, although not in the Irvine sample. The paper discusses the possible influence of the selection criteria on these differential results. The Irvine sample selected subjects that met the DSM-IV combined subtype diagnosis, whereas the Toronto sample included all subtypes. Analysis of the DSM-IV subtypes in the Toronto sample indicated that the differential results were not attributable to ADHD subtype. Differences in ethnicity, differential medication response, and other clinical characteristics of the samples cannot be ruled out at this time. Quantitative analysis of the dimensions of hyperactivity/impulsivity and inattention in the Toronto sample found that both behavioral traits were associated with SNAP25. Our findings continue to support SNAP25 in the susceptibility to ADHD.

Animals↗

PubMed2005

Association of the calcyon gene (DRD1IP) with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a childhood-onset disorder characterized by marked inattention, hyperactivity and impulsivity. The dopaminergic system has been hypothesized to be involved in the development of ADHD. Positive associations have been found for the dopamine receptors D1 and D5 genes, suggesting that other genes involved in D1/D5 signalling may also contribute to ADHD. In this study, we tested the calcyon gene (DRD1IP), which encodes a brain-specific D1-interacting protein involved in D1/D5 receptors calcium signalling, for association with ADHD. The inheritance of nine polymorphisms in the calcyon gene was examined in a sample of 215 nuclear families, with 260 affected children, using the transmission/disequilibrium test. The most common haplotype, designated C1, demonstrated significant evidence for excess transmission. Quantitative trait analyses of this haplotype showed significant relationships with both the inattentive (parent's rating, P=0.006; teacher's rating, P=0.003) and hyperactive/impulsive (parent's rating, P=0.004) dimensions of the disorder. Two of the nine marker alleles included in haplotype C1, rs4838721A located approximately 10 kb 5' of the gene and rs2275723C located 10 bp upstream of the exon 5 acceptor splice site, also showed significant evidence for association when analysed individually. As these two variants are not predicted to alter calcyon function, we screened the gene exons by sequencing. No variation in the coding region was identified, suggesting that a causal variant allele resides elsewhere in a regulatory sequence of the gene. These findings support the proposed involvement of the calcyon gene in ADHD and implicate haplotype C1 as containing a risk allele.

Adolescent↗

PubMed2005

Genetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder that affects approximately 1% of the general population. The human leukocyte antigen (HLA) system has been implicated in several genetic studies of SCZ. The myelin oligodendrocyte glycoprotein (MOG) gene, which is located close to the HLA region, is considered a candidate for SCZ due to its association with white matter abnormalities and its importance in mediating the complement cascade. Four polymorphisms in the MOG gene (CA)n (TAAA)n, and two intronic polymorphisms, C1334T and C10991T, were investigated for the possibility of association with SCZ using 111 SCZ proband and their families. We examined the transmission of the alleles of each of these polymorphisms with the transmission disequilibrium test. We did not observe significant evidence for biased transmission of alleles at the (CA)n (chi2=2.430, 6 df, P=0.876) (TAAA)n (chi2=3.550, 5 df, P=0.616), C1334T (chi2=0.040, 1 df, P=0.841) and C10991T (chi2=0.154, 1 df, P=0.695) polymorphisms. Overall haplotype analysis using the TRANSMIT program was also not significant (chi2=7.954, 9 df, P=0.539). Furthermore, our results comparing mean age at onset in the genotype groups using the Kruskal-Wallis Test were not significant. Our case-control analyses (182 cases age-, sex- and ethnicity-matched with healthy controls) and combined z-score [(CA)n: z-score=-1.126, P=0.130; (TAAA)n: z-score=-0.233, P=0.408; C1334T: z-score=0.703, P=0.241; C10991T: z-score=0.551, P=0.291] were also not significant. Although our data are negative, the intriguing hypothesis for MOG in SCZ may warrant further investigation of this gene.

Adult↗

PubMed2004

Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals. BDNF gene polymorphisms have been associated with bipolar disorder. We tested two genetic polymorphisms of BDNF for their association with childhood-onset mood disorders (COMD) within the context of a case-control design. Two BDNF polymorphisms, a dinucleotide repeat (GT)(n), and a single nucleotide polymorphism (SNP) in the coding region, val66met, were genotyped in 99 adults with a history of COMD and matched psychiatrically healthy controls. A genomic control (GC) method was used to evaluate population substructure. Alleles at (GT)(n) were highly associated with COMD in this sample (chi(2) = 17.8; d.f. = 5; P = 0.0032). The odds of carrying the 168 bp allele were 3.94 times greater for cases than controls (CI = 1.72-9.04). Alleles of val66met were not significantly associated with COMD. GC analysis suggested population substructure was not a confounder of association. Analysis of haplotypes, in which (GT)(n) was treated as a binary variable (long vs. short alleles), provided significant evidence that the haplotype val/short contributes to liability to COMD. The BDNF (GT)(n) marker and the val/short haplotype are associated with COMD in this sample, in accordance with the previously described neurotrophic hypothesis of depression and some previous studies of association for bipolar disorder and neuroticism.

Adolescent↗

PubMed2004

Association study of serotonin-2A receptor gene polymorphism and panic disorder in patients from Canada and Germany.

The T102C serotonin-2A (5-HT2A) receptor gene polymorphism has been studied extensively in a number of complex psychiatric conditions with mixed results. Recently a genetic association has been described between this polymorphism and panic disorder in a Japanese sample. To evaluate the impact of the T102C polymorphism in panic disorder we genotyped triad families (panic disorder patient and parents), and cases with controls in Canadian and German samples. No significant transmission disequilibrium was observed between the alleles of the T102C 5-HT2A receptor gene polymorphism and panic disorder, nor was a significant excess of either allele found in the case control analysis. Our data suggest thus that this polymorphism is unlikely to play a major role in the pathogenesis of panic disorder.

Alleles↗

PubMed2004

Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11.

As part of an extensive study in the Portuguese Island population of families with multiple patients suffering from bipolar disorder and schizophrenia, we performed an initial genome-wide scan of 16 extended families with bipolar disorder that identified three regions on chromosomes 2, 11, and 19 with genome-wide suggestive linkage and several other regions, including chromosome 6q, also approached suggestive levels of significance. Dick et al. [2003: Am J Hum Genet 73:107-114] recently reported in a study of 250 families with bipolar disorder a maxLOD score of 3.61 near marker D6S1021 on chromosome 6q. This study replicates this finding having detected a peak NPL = 2.02 (P = 0.025) with the same marker D6S1021(104.7 Mb). Higher-density mapping provided additional support for loci on chromosome 6 including marker D6S1021 with an NPL = 2.59 (P = 0.0068) and peaking at marker D6S1639 (125 Mb) with an NPL = 3.06 (P = 0.0019). A similar pattern was detected with higher-density mapping of chromosome 11 with an NPL = 3.15 (P = 0.0014) at marker D11S1883 (63.1 Mb). Simulations at the density of our fine mapping data indicate that less than 1 scan out of 10 would find two such scores genome-wide in the same scan by chance. Our findings provide additional support for a susceptibility locus for bipolar disorder on 6q, as well as, suggesting the importance of denser scans. Published 2004 Wiley-Liss, Inc.

Bipolar Disorder↗

PubMed2004

Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22.

We performed a linkage analysis on 25 extended multiplex Portuguese families segregating for bipolar disorder, by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the GeneChip Human Mapping 10K Array (HMA10K). Of these families, 12 were used for a direct comparison of the HMA10K with the traditional 10-cM microsatellite marker set and the more dense 4-cM marker set. This comparative analysis indicated the presence of significant linkage peaks in the SNP assay in chromosomal regions characterized by poor coverage and low information content on the microsatellite assays. The HMA10K provided consistently high information and enhanced coverage throughout these regions. Across the entire genome, the HMA10K had an average information content of 0.842 with 0.21-Mb intermarker spacing. In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays. The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11.

Bipolar Disorder↗

PubMed2004

PedSplit: pedigree management for stratified analysis.

SUMMARY: PedSplit facilitates pedigree management for gene-gene interaction and sex specific tests for increased homogeneity within subgroups. PedSplit also provides a simple approach for calculating haplotype relative risk and generating internal 'controls'. AVAILABILITY: Executables, C++ source code and documentation for PedSplit can be downloaded from http://www.pharmacogenetics.ca in the links and software section.

Algorithms↗

PubMed2004

Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis.

Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31-5q35 with strong linkage (NPL=3.09, P=0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL=3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL=3.28 (P=0.00066) at markers D5S2112-D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL=3.03, P=0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases. Molecular Psychiatry (2004) 9, 213-218. doi:10.1038/sj.mp.4001418 Published online 30 December 2003

Azores↗