Biomedical subjects

M A Crocq

Publications and source records attributed to M A Crocq.

At least 19 recordsLinked to original sources

PubMed1999

Trend for an association between schizophrenia and D3S1310, a marker in proximity to the dopamine D3 receptor gene.

There is considerable controversy regarding a putative association between schizophrenia and a biallelic BalI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3), although meta-analyses of published data suggest an association. If such an association exists, it may be detectable at markers physically close to DRD3. Accordingly, we conducted a case-control association study using D3S1310, a short tandem repeat polymorphism located approximately 700 kb telomeric to DRD3 on chromosome 3q13.3. The subjects were Swedish patients with schizophrenia (DSM III-R criteria, n = 110) and screened adult controls (n = 83). A trend for a negative association with the 141 bp allele was detected (chi2 = 7.6, d.f. = 1, P = 0.006; odds ratio 0.46, 95% confidence intervals 0.26, 0.81). However, following corrections for multiple comparisons using subgroups (n = 15) the difference was not significant. Also, due to the risk for population stratification in case-control association studies the results must be treated as tentative. If replicated the results may lend further support for the proposition of an association between schizophrenia and DRD3 or a gene in close proximity to DRD3 on chromosome 3q.

Adult↗

PubMed1999

Thyroid axis activity and serotonin function in major depressive episode.

Recent studies in depression have reported alterations in both hypothalamic-pituitary-thyroid (HPT) axis activity and serotonin (5-HT) function; however, the functional relationships between the two systems have not been well defined in patients with major depressive episode. Thyrotropin (TSH) response to 0800 and 2300 h protirelin (TRH) challenges, and adrenocorticotropic hormone (ACTH), cortisol, and prolactin (PRL) responses to D-fenfluramine (D-FEN), a specific 5-HT releasing/uptake-inhibiting agent, were examined in 60 drug-free DSM-IV major depressed inpatients and 20 hospitalized controls. Compared with controls, patients showed lower basal serum 2300 h TSH, 2300 h maximum increment in serum TSH above baseline (delta TSH) and difference between 2300 h delta TSH and 0800 h delta TSH (delta delta TSH) levels. The hormonal responses to D-FEN (i.e. delta ACTH, delta cortisol and delta PRL) were interrelated. No significant difference in basal and post-D-FEN ACTH, cortisol or PRL values were found between controls and patients. A negative relationship between hormonal responses to D-FEN and 2300 h delta TSH and delta delta TSH values was observed in the depressed group. When patients were classified on the basis of their delta TSH test status, patients with reduced delta delta TSH values (i.e. with HPT axis abnormality) had hormonal D-FEN responses comparable to those of controls. Patients with normal delta delta TSH values (i.e. without HPT axis abnormality) showed lower ACTH, cortisol and PRL responses to D-FEN than controls and patients with abnormal delta delta TSH values. These results suggest that: (1) pathophysiological mechanisms other than 5-HT dysregulation may be involved in TSH blunting in major depressed patients; (2) 5-HT function is reduced in some depressed patients, especially those without HPT axis abnormality; and (3) HPT dysregulation may be regarded as a compensatory mechanism for diminished central 5-HT activity.

Adolescent↗

PubMed1999

Association between hSKCa3 and schizophrenia not confirmed by transmission disequilibrium test in 193 offspring/parents trios.

A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.

Female↗

PubMed1998

Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders.

In a population-based association study, we tested the hypothesis that allelic variants of the human serotonin transporter (5-HTT) gene confer susceptibility to mood disorders. Both a biallelic repeat polymorphism in the 5' promotor region that differentially modulates gene expression and a second intron variable-number-tandem-repeat (VNTR) marker were genotyped in 294 controls and 115 patients with mood disorders. Subjects were of West European descent and included 36 patients with major depressive disorder (MDD) and 79 patients with bipolar I disorder (BD). No significant differences in genotype or allele frequencies were found at either locus between controls and combined patients, nor between controls and MDD or BD patients separately. Thus, our data do not support the association between depressive disorder and a nine-repeat allelic variant of the 5-HTT VNTR marker recently reported by Ogilvie et al. (Lancet 347:731-733, 1996). More importantly, no association between alleles conveying functional differences in 5-HTT gene expression and MDD or BD could be found. Taken together, our data suggest that the 5-HTT gene is not commonly involved in the susceptibility to mood disorders.

Alleles↗

PubMed1998

The human small conductance calcium-regulated potassium channel gene (hSKCa3) contains two CAG repeats in exon 1, is on chromosome 1q21.3, and shows a possible association with schizophrenia.

Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. We have previously identified the human small conductance calcium-activated potassium channel gene (hSKCa3) which has two tandemly arranged CAG repeats in its 5' region. Here we have isolated the first genomic clones containing the gene and have shown that both repeats are in exon 1. Homology to the previously localized sequence tagged site G16005 indicated that the gene may be on chromosome 22q, however using polymerase chain reaction amplification of somatic cell hybrid DNA and fluorescence in situ hybridization of two P1 artificial chromosome clones, we physically localized the gene to chromosome 1q21.3. We previously found an association between the highly polymorphic second (more 3') CAG repeat and schizophrenia in 98 patients and 117 controls. We have now genotyped an additional 19 patients with schizophrenia and have performed statistical analyses on the entire group of patients and controls to investigate the possible effect of age of onset, family history, and gender of the patients on the observed association. None of these factors were found to influence the results. Both CAG repeats have been typed in 86 bipolar I disorder patients, and no significant difference in allele distribution was observed between our bipolar disorder patients and controls.

Animals↗

PubMed1998

Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder?

Many human hereditary neurodegenerative diseases are caused by expanded CAG repeats, and anonymous CAG expansions have also been described in schizophrenia and bipolar disorder. We have isolated and sequenced a novel human cDNA encoding a neuronal, small conductance calcium-activated potassium channel (hSKCa3) that contains two arrays of CAG trinucleotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 repeats. The overall allele frequency distribution is significantly different in patients with schizophrenia compared to ethnically matched controls (Wilcoxon Rank Sum test, P=0.024), with CAG repeats longer than the modal value being over-represented in patients (Fisher Exact test, P=0.0035). A similar, non-significant, trend is seen for patients with bipolar disorder. These results provide evidence for a possible association between longer alleles in the hSKCa3 gene and both of these neuropsychiatric diseases, and emphasize the need for more extensive studies of this new gene. Small conductance calcium-activated K+ channels play a critical role in determining the firing pattern of neurons. These polyglutamine repeats may modulate hSKCa3 channel function and neuronal excitability, and thereby increase disease risk when combined with other genetic and environmental effects.

Alleles↗

PubMed1998

A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia.

We performed a meta-analysis of over 30 case-control studies of association between schizophrenia and a bi-allelic, Bali polymorphism in exon 1 of the dopamine D3 receptor gene. We observed a significant excess of both forms of homozygote in patients (P = 0.0009, odds ratio (OR) = 1.21, 95% Confidence Interval (CI) = 1.07-1.35) in the combined sample of 5351 individuals. No significant heterogeneity was detected between samples and the effects did not appear to be the product of publishing bias. In addition we undertook an independent, family-based association study of this polymorphism in 57 parent/proband trios, taken from unrelated European multiplex families segregating schizophrenia. A transmission disequilibrium test (TDT) showed a significant excess of homozygotes in schizophrenic patients (P = 0.004, odds ratio (OR) = 2.7, 95% CI = 1.35-5.86). Although no significant allelic association was observed, a significant association was detected with the 1-1 genotype alone (P = 0.02, OR = 2.32, 95% CI = 1.13-4.99). In addition when the results of the family-based association study were included in the meta-analysis, the homozygosity effect increased in significance (P = 0.0002, OR = 1.23, 95% CI = 1.09-1.38). The results of the meta-analysis and family-based association study provide independent support for a relationship between schizophrenia and homozygosity at the Bali polymorphism of the D3 receptor gene, or between a locus in linkage disequilibrium with it.

Alleles↗

PubMed1998

No association between the tyrosine hydroxylase microsatellite marker HUMTH01 and schizophrenia or bipolar I disorder.

Linkage and association studies have implicated the involvement of the tyrosine hydroxylase (TH) gene on chromosome 11p15 in schizophrenia and bipolar disorder (BPD). An association of BPD with a polymorphic tetranucleotide repeat, HUMTH01, located in the first intron of the human TH gene has been reported. Subsequently a rare allele, Ep ([TCAT]10) of this microsatellite marker has been found in French and Tunisian schizophrenic patients only. We have genotyped a different sample of unrelated French schizophrenic and BPD patients from Alsace and matched controls for this polymorphic tetranucleotide repeat sequence. The Ep allele was insignificantly more common in controls than in schizophrenic patients, thus not showing a particular association with schizophrenia. In addition, analysis of the segregation of the Ep allele in the family of one of the schizophrenic patients showed no transmission of this allele from the healthy mother to her schizophrenic daughter. Nevertheless, we did observe a non-significant trend towards an association between HUMTH01 allele D ([TCAT]9) and schizophrenia (Fisher's exact test, p = 0.053). No association was apparent between HUMTH01 and BPD Psychiatr Genet.

Adult↗

PubMed1997

Analysis of the CAG repeats in the SCA1 and B37 genes in schizophrenic and bipolar I disorder patients: tentative association between B37 and schizophrenia.

We have genotyped unrelated French Alsatian schizophrenic and bipolar I disorder (BPD) patients and matched controls for the polymorphic CAG repeats within the genes for spinocerebellar ataxia type 1 (SCA1) and dentatorubral-pallidoluysian atrophy (B37), in order to test their possible involvement in these disorders. No alleles with abnormally expanded repeats were found in either gene in patients and controls. Differences in allele and genotype frequencies for the SCA1 CAG repeat between patients and controls were not significant, thus providing no support for its role as a possible positional candidate gene for schizophrenia and BPD in our patients. Chi square testing revealed a significant result (P = 0.019) for an association between the B37 CAG repeat on chromosome 12p and schizophrenia. This result was more significant when only schizophrenics with a positive family history were compared with controls (P = 0.0001). The frequencies of alleles with 14, 12, and 15 CAG repeats differed the most, respectively, between schizophrenics and controls. When choosing the median of the B37 allele distribution (15 CAG repeats) as a threshold, there were significantly more controls than schizophrenics in the group with longer alleles (15 or more repeats) and more schizophrenics with shorter alleles (P = 0.002 by Fisher exact test). No particular genotype was associated with schizophrenia. This result possibly indicates linkage disequilibrium with another locus on chromosome 12p and therefore deserves further attention. No association was found between the B37 CAG repeat and patients with BPD.

Adult↗

PubMed1997

HPA axis dysfunction in depression: correlation with monoamine system abnormalities.

Abnormality of the hypothalamic-pituitary-adrenal (HPA) axis has been one of the most consistently demonstrated biological markers of depressive disorder. It has also been proposed that abnormality of monoamine function plays a role in the pathogenesis of the disorder. In order to examine the interrelationships of the HPA axis with the dopaminergic, noradrenergic, and serotoninergic systems, we studied, in 52 medication-free inpatients with DSM-IV nonpsychotic major depressive disorder, the relationship between dexamethasone suppression test (DST) status and a series of multihormonal responses to apomorphine (APO), clonidine (CLO), and D-fenfluramine (FEN) tests. DST nonsuppressors did not present any difference compared with suppressors in growth hormone (GH) and cortisol stimulation by APO suggesting that a chronic elevation of cortisol did not lead to an alteration of dopaminergic activity in this population of nonpsychotic depressed inpatients. Cortisol and prolactin responses to FEN were comparable in nonsuppressors and in suppressors. In contrast, GH response to CLO was lower in DST nonsuppressors than in suppressors (p < .03), suggesting that the HPA abnormality indicated by a positive DST may be related to alpha 2-adrenoreceptor dysfunction.

Adrenergic alpha-Agonists↗

PubMed1997

A novel allelic variant of the human serotonin transporter gene regulatory polymorphism.

Allelic variation of the human serotonin transporter gene (SLC6A4) has recently been shown to modulate anxiety-related traits. A tandemly repeated sequence in close proximity to the promoter was found to be represented by a long (L) and short (S) variant, differentially modulating gene expression in vitro. Specifically, allele S, generated by a deletion of 44 bp involving repeats VI to VIII, reduced transcriptional efficiency, gene expression, and 5-hydroxytryptamine uptake and was associated with increased neuroticism scores. We have now identified a novel allelic variant of this promoter-linked polymorphism that is significantly larger than the L allele and which we have designated allele XL (for "extra large"). Sequence analysis revealed that XL arose through duplication of an internal segment composed of repeat elements VI to IX, comprising 85 bp in total, and, most notably, including the segments deleted in the S allele. Additional allelic variants larger than human allele L were observed predominantly in various nonhuman primates. Preliminary data indicated that these variable allelic extensions similarly originate from this specific repeat region. These allelic variants may serve as a valuable model system to further elucidate the relationship between repeat structure, regulatory properties, and behavioral correlates. Finally, allelic variants were found to vary significantly among different human populations, with allele XL being uniquely present in individuals of African origin, allele L most frequent in Africans and Caucasians of Western European descent, and allele S most abundant in East Asians.

Africa↗

PubMed1996

Dopamine-related genes and their relationships to monoamine metabolites in CSF.

Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.

Adult↗

PubMed1996

Growth hormone response to clonidine and the cortisol response to dexamethasone in depressive patients.

The dexamethasone suppression test (DST) and the clonidine stimulation test (CST) were studied in 47 depressed patients. Issues addressed included (1) the usefulness of both tests as markers of major depression; (2) the relationship between the two tests and the pathophysiology underlying this relationship; and (3) the psychopathological correlates of both tests. The widely reported link between abnormal DST results and melancholic depression was confirmed. The DST and the CST showed extensive overlap, suggesting a relationship in major depression between the biological abnormalities indexed by each test (i.e., hypothalamic-pituitary-adrenal axis and noradrenergic system). Finally, the psychopathological correlates of various subgroups categorized on the basis of test responses (e.g., normal test results, blunted CST results, and both abnormal DST and CST results) confirmed significant differences between groups on two items of the Hamilton Rating Scale for Depression: psychic anxiety and somatic anxiety. The results suggest that particular patterns of neuroendocrine abnormalities may be associated with particular profiles of depressive symptomatology.

Adrenergic Agonists↗

PubMed1996

Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia.

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distribution of the Msp I and Bal I genotypes were not independent in 297 individuals (chi 2 = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism (chi 2 = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls (chi 2 = 5.3, df = 1, P = 0.02) and found more important in mal than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls (chi 2 = 0.06, df = 1, P = 0.80, chi 2 = 0.22, df = 1, P = 0.90 and chi 2 = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3' part of the gene may explain the discrepant results obtained with the two polymorphisms.

Animals↗

PubMed1996

Effect of antidepressant medication on morning and evening thyroid function tests during a major depressive episode.

BACKGROUND: This study sought to determine whether changes in thyroid function that may occur during antidepressant treatment are related to a direct effect of the drug on the thyroid axis or to a change in clinical state. METHODS: Morning and evening thyroid function was evaluated in 30 euthyroid inpatients who met DSM-IV criteria for major depressive episode, by determination of free triiodothyronine, free thyroxine, and thyrotropin levels before and after 8 AM and 11 PM protirelin challenges (200 micrograms intravenously), on the same day. Results at baseline were compared with those after 1 month of antidepressant treatment with either amitriptyline hydrochloride, fluoxetine hydrochloride, or toloxatone. RESULTS: Clinical efficacy and effects on thyroid function did not differ across the 3 antidepressant drugs. Compared with pretreatment values, significant reductions in basal serum 8 AM free thyroxine, 11 PM free thyroxine, and 8 AM free triiodothyronine levels and increases in 11 PM maximum increment in plasma thyrotropin level and the difference between 11 PM and 8 AM maximum increment in plasma thyrotropin values were observed in responders (n = 11) but not in partial responders (n = 6) or nonresponders (n = 13). Moreover, nonresponders exhibited lower pretreatment 11 PM thyrotropin values (basal and maximal increment above basal) than responders. CONCLUSIONS: The results suggest that (1) changes in thyroid function are related to clinical recovery rather than to a direct effect of the antidepressant drug and (2) patients with the lowest pretreatment evening thyrotropin secretion have the lowest rate of antidepressant response, and this may contribute to treatment resistance.

Adult↗

PubMed1995

Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients.

We have examined the hypothesis that a variable number of tandem repeats in the third cytoplasmic loop of the dopamine D4 receptor influences clinical response to clozapine using a sample of 189 schizophrenic patients. Alleles of the 48-bp repeat, which range from two to ten copies in the normal human population, were analysed by the polymerase chain reaction using genomic DNA as template. Association between these alleles and response to clozapine was tested using the difference in pre- and post-treatment GAS scores as a measure of response. We found no statistically significant variation between genotypic groups and response by analysis of variance. We conclude that the variation of the number of 48-bp repeats alone does not determine response to clozapine. Larger studies are underway to determine if there is a more subtle relationship with sequence variation within the repeats or at other polymorphic sites within the gene that may provide evidence for a component of clozapine's action being at D4 receptors.

Alleles↗

PubMed1995

Multihormonal responses to apomorphine in mental illness.

The neuroendocrine responses to subcutaneous (SC) administration of the dopamine (DA) agonist apomorphine (APO) hydrochloride (0.75 mg) were studied in a large group of subjects: 110 drug-free inpatients with either DSM-III-R schizophrenia (SCZ, n = 46), schizoaffective disorder (SAD, n = 14), or major depressive episode (MDE, n = 50), plus 18 hospitalized controls. Compared to a saline test, APO induced a significant increase of growth hormone (GH), adrenocorticotropin (ACTH), and cortisol (COR) release and a decrease in prolactin (PRL) secretion. No change in thyrotropin (TSH) levels was observed. In the total sample the extents of ACTH, COR and GH responses were correlated, but in the group of 88 subjects who exhibit a normal GH stimulation this correlation disappeared. This discrepancy suggests that APO-induced ACTH and COR stimulation may be mediated by pathways different from those mediating GH stimulation. According to diagnostical categories, we found significant lower ACTH and COR stimulation in the schizophrenic group and in patients with SAD, compared with that among controls or depressed patients. We found also a significant difference between subgroups of schizophrenic patients. These results agree with the hypothesis that different aspects of psychosis might involve different subtypes of DA-receptors with different localizations and sensitivities.

Adrenocorticotropic Hormone↗

PubMed1995

Cytochrome P4502D6 genotype does not determine response to clozapine.

1. The atypical antipsychotic drug clozapine, used in the treatment of resistant schizophrenia, is metabolized partly by the hepatic cytochrome P450 enzyme CYP2D6. Two phenotypes with respect to the activity of the enzyme are recognized (extensive metabolisers (EM) and poor metabolisers (PM)), resulting from allelic variation in the gene, CYP2D6. 2. Genotype was determined in 123 schizophrenic patients currently being treated with clozapine, in order to determine if EM or PM status influences response to this drug. Patients were divided into responders and non-responders using the Global Assessment Scale, and genotyped for the A and B poor metaboliser mutations by digesting PCR products with HpaII or BstNI. 3. Fifty-nine patients were heterozygous for allele B and for allele A. Eight patients were determined as poor metabolisers since they were homozygous either for A and B. Poor metabolisers were equally distributed between responders and nonresponders and no correlation between CYP2D6 alleles and response to clozapine was found. 4. The results are consistent with recent findings showing that CYP1A2, rather than CYP2D6, is the major enzyme responsible for the metabolism of clozapine.

Alleles↗