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W H Berrettini

Publications and source records attributed to W H Berrettini.

At least 37 records · Page 2Linked to original sources
PubMed2000

Lack of association between temporal lobe epilepsy and a novel polymorphism in the alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase.

Genetic linkage studies in rodents and humans have identified specific chromosomal regions harboring seizure susceptibility genes. We have identified a novel polymorphism in the human alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase (NaK-pump), a candidate gene for human temporal lobe epilepsy (TLE) based on its chromosomal location and function in ion homeostasis. The polymorphism consists of a four base pair insertion 12 base pairs upstream of the start of exon 2. We performed an association study between this polymorphism and TLE. Our study did not find a significant difference in the frequency of this polymorphism between TLE patients and controls, indicating that this variation is not a major susceptibility factor. However, since the number of patients studied so far is small and the functional consequence of the polymorphism is unknown, the variation may yet be found to play a minor role in increased risk for seizure susceptibility. In contrast to the findings in TLE patients and controls, we did find a significant difference in the frequency of the variation between African Americans and persons of European descent. This finding demonstrates the potential effect of population stratification on studies of this type and supports the growing use of parental and familial samples for controls in association studies. Further study of this polymorphism is warranted as it may be involved in other disease processes for which there are known ethnic-specific susceptibilities. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:79-83, 2000.

Base Sequence↗
PubMed2000

Susceptibility loci for bipolar disorder: overlap with inherited vulnerability to schizophrenia.

Genetic epidemiological studies reveal that relatives of bipolar probands are at increased risk for recurrent unipolar, bipolar, and schizoaffective disorders, whereas relatives of probands with schizophrenia are at increased risk for schizophrenia, schizoaffective, and recurrent unipolar disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed bipolar susceptibility loci for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11-13, and Xq26. Studies of schizophrenia kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11-13, both of which are implicated in susceptibility to bipolar disorder. Similarly, confirmed schizophrenia vulnerability loci have been mapped, too, for 6p24, 8p, and 13q32. Strong statistical evidence for a 13q32 bipolar susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two groups of disorders may not be as distinct as current nosology suggests.

Bipolar Disorder↗
PubMed2000

Cocaine intake by rats correlates with cocaine-induced dopamine changes in the nucleus accumbens shell.

Extracellular dopamine levels were determined by microdialysis in the core and shell of the nucleus accumbens and the frontal cortex of rats before and after an injection of cocaine (20 mg/kg, IP). After removal of the probes, these same animals were then tested for their voluntary intake of cocaine using the two-bottle, free-choice paradigm. Baseline dopamine levels and their responses to an injection of cocaine differed among the three brain areas. No significant correlations were found between baseline dopamine levels in any of the three brain regions and the voluntary cocaine consumption. A significant negative correlation was found between cocaine-induced increases in extracellular dopamine in the shell of the nucleus accumbens and the voluntary intake of cocaine (r = -0.73, p < 0.01). No such correlations were observed in the accumbens core region or the frontal cortex. These results provide further evidence of the role of the accumbal shell region in cocaine preference, and indicate that cocaine-induced increases in dopamine levels play a role in oral cocaine self-administration or preference. In addition, this relatively novel approach in using the same animals for both cocaine induced neurotransmitter responses and cocaine preference studies can also be applied for the study of other neurotransmitters and drugs of abuse.

Animals↗
PubMed2000

Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2).

Recently, we cloned the human myo-inositol monophosphatase 2 (IMPA2) cDNA and established its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder. Because the myo-inositol monophosphatase enzyme has been shown to be inhibited by lithium, an effective therapeutic agent for bipolar disorder, IMPA2 is a plausible positional and functional candidate gene. To permit comprehensive screening for variants we characterized the genomic structure and isolated the potential promoter of IMPA2. The gene was found to encode eight exons spanning;27 kb. The proximal 1-kb 5' flanking region did not contain an obvious TATA box but multiple potential binding sites for Sp1 and consensus motifs for AP2 and other transcription factors were evident. Sequencing of the coding region and splice junctions in unrelated bipolar disorder patients detected novel variants. A missense mutation in exon 2, His76Tyr, was found in one patient. His76 is evolutionarily conserved and replacement with Tyr introduces a potential site for phosphorylation. The other polymorphisms included an RsaI polymorphism, IVS1-15G>A, and a T --> C silent mutation in the third nucleotide of codon 53 in exon 2. By Fisher's exact test the silent mutation showed a trend for association (P = 0.051) with bipolar disorder suggesting that further scrutiny of this gene is warranted.

Alternative Splicing↗
PubMed2000

Identification of candidate genes for psychiatric disorders on 18p11.

Linkage studies have suggested a locus for bipolar disorder as well as schizophrenia in the pericentric region of chromosome 18. Several candidate genes have been identified in the region including ACTH, IMP, and G(olf), however no reports of mutations in families showing linkage to the 18p11 locus have been reported. Recently, mild linkage disequilibrium has been observed with a polymorphic marker that maps within the G(olf) gene and schizophrenia in families from Germany and Israel, suggesting that a gene mapping near G(olf) may be involved in psychiatric disorders. A BAC and cosmid contig around the G(olf) locus has been generated and BAC clones were used for cDNA selection experiments. Several novel genes have been identified which are expressed in the brain. These genes may be possible candidate genes for psychiatric illness.

Bipolar Disorder↗
PubMed2000

Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia.

The sequence and genomic organization of the human Golfalpha (GNAL) gene were determined. The human GNAL gene was found to contain 12 coding exons, and it spans over 80 kb on chromosome 18p11. 5' RACE analysis suggested an additional transcription initiation start site. Sequence analysis of the putative promoter region revealed conserved binding sites for several transcription factors. Sequence analysis of the 3'-untranslated region revealed the presence of two Alu sequences and two polyadenylation signals. 3' RACE analysis confirmed the functionality of the most downstream poly-a signal. The human GNAL was found to be expressed as a single transcript of about 5.9 kb in the brain. One highly informative dinucleotide repeat was found in intron 5. Additionally, a processed pseudogene for asparagine synthetase was found about 6 kb upstream of the GNAL gene. Knowledge of the sequence and structure of the human GNAL gene provides essential information for further analysis of the GNAL locus at chromosome 18p11 which has been linked to bipolar disorder and schizophrenia.

3' Untranslated Regions↗
PubMed2000

Temperament and character in women with anorexia nervosa.

The present study examined temperament differences among anorexia nervosa (AN) subtypes and community controls, as well as the effect of body weight on personality traits in women with AN. Temperament and Character Inventory (TCI) scores were compared between 146 women with restrictor-type AN (RAN), 117 women with purging-type AN (PAN), 60 women with binge/purge-type AN (BAN), and 827 community control women (CW) obtained from an archival normative database. Women with AN scored significantly higher on harm avoidance and significantly lower on cooperativeness than CW. Subtype analyses revealed that women with RAN and PAN reported the lowest novelty seeking, RAN women the highest persistence and self-directedness, and PAN women the highest harm avoidance. Body mass index had a nominal effect on subgroup differences, suggesting that personality disturbances are independent of body weight. Findings suggest that certain facets of temperament differ markedly between women with AN, regardless of diagnostic subtype, and controls. More subtle temperament and character differences that were independent of body weight emerged that distinguish among subtypes of AN.

Adult↗
PubMed2000

Genetics of psychiatric disease.

Genetic epidemiologic studies reveal that relatives of bipolar (BIP) probands are at increased risk for recurrent unipolar (RUP), BIP, and schizoaffective (SA) disorders, while relatives of schizophrenia (SZ) probands are at increased risk for SZ, SA, and RUP disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed susceptibility loci for BIP disorder for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11-13, and Xq26. Studies of SZ kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11-13, both of which are implicated in susceptibility to BIP disorder. Similarly, confirmed SZ vulnerability loci have been mapped for 6p24, 8p and 13q32. Strong statistical evidence for a 13q32 BIP susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two group of disorders may not be so distinct as current nosology suggests.

Bipolar Disorder↗
PubMed2000

Perfectionism in anorexia nervosa: variation by clinical subtype, obsessionality, and pathological eating behavior.

OBJECTIVE: The purpose of this study was to examine the role of perfectionism as a phenotypic trait in anorexia nervosa and its relevance across clinical subtypes of this illness. METHOD: The Multidimensional Perfectionism Scale and the perfectionism subscale of the Eating Disorder Inventory were administered to 322 women with a history of anorexia nervosa who were participating in an international, multicenter genetic study of anorexia nervosa. All participants were additionally interviewed with the Yale-Brown Obsessive Compulsive Scale and the Yale-Brown-Cornell Eating Disorder Scale. Mean differences on dependent measures among women with anorexia nervosa and comparison subjects were examined by using generalized estimating equations. RESULTS: Persons who had had anorexia nervosa had significantly higher total scores on the Multidimensional Perfectionism Scale than did the healthy comparison subjects. In addition, scores of the anorexia subjects on the Eating Disorder Inventory-2 perfectionism subscale exceeded Eating Disorder Inventory-2 normative data. For the anorexia nervosa participants, the total score on the Multidimensional Perfectionism Scale and the Eating Disorder Inventory-2 perfectionism subscale score were highly correlated. Total score on the Multidimensional Perfectionism Scale was also significantly related to the total score and the motivation-for-change subscale score of the Yale-Brown-Cornell Eating Disorder Scale. CONCLUSIONS: These data show that perfectionism is a robust, discriminating characteristic of anorexia nervosa. Perfectionism is likely to be one of a cluster of phenotypic trait variables associated with a genetic diathesis for anorexia nervosa.

Adolescent↗
PubMed1999

Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice.

DBA/2J (D2) and C57BL/6J (B6) mice exhibit differential sensitivity to seizures induced by various chemical and physical methods, with D2 mice being relatively sensitive and B6 mice relatively resistant. We conducted studies in mature D2, B6, F1, and F2 intercross mice to investigate behavioral seizure responses to pentylenetetrazol (PTZ) and to map the location of genes that influence this trait. Mice were injected with PTZ and observed for 45 min. Seizure parameters included latencies to focal clonus, generalized clonus, and maximal seizure. Latencies were used to calculate a seizure score that was used for quantitative mapping. F2 mice (n = 511) exhibited a wide range of latencies with two-thirds of the group expressing maximal seizure. Complementary statistical analyses identified loci on proximal (near D1Mit11) and distal chromosome 1 (near D1Mit17) as having the strongest and most significant effects in this model. Another locus of significant effect was detected on chromosome 5 (near D5Mit398). Suggestive evidence for additional PTZ seizure-related loci was detected on chromosomes 3, 4, and 6. Of the seizure-related loci identified in this study, those on chromosomes 1 (distal), 4, and 5 map close to loci previously identified in a similar F2 population tested with kainic acid. Results document that the complex genetic influences controlling seizure response in B6 and D2 mice are partially independent of the nature of the chemoconvulsant stimulus with a locus on distal chromosome 1 being of fundamental importance.

Animals↗
PubMed1999

A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2.

Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on approximately 396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0. 000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2. 67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0. 00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia.

Bipolar Disorder↗
PubMed1998

Genetic influences on electrical seizure threshold.

C57BL/6J (B6) and DBA/2J (D2) mice have been characterized previously as seizure-resistant and seizure-sensitive, respectively, a distinction based primarily upon a differential response to the convulsant effects of various drugs. In the present study, electroconvulsive shock (ECS) was used to assess maximal electroshock threshold (MET) in B6, D2 and hybrid mice. Results revealed that D2 mice have a significantly lower MET compared to B6 mice. There was also a significant gender effect for B6 and F2 mice with females exhibiting a lower MET compared to males. METs for F1 and F2 intercross mice were intermediate between the two parental strains. The difference in variance between F2 and F1 generation mice indicated that about three-quarters of the total variance is due to genetic influence. Taken together, results of this study suggest that the large difference in MET between B6 and D2 mice is a highly heritable trait which may yield to genetic dissection through use of quantitative trait locus mapping.

Animals↗
PubMed1998

Serotonin transporter (5-HTT) gene and bipolar affective disorder.

Interactions with antidepressants, as well as other biochemical evidence, implicate the serotonin transporter 5-HTT in the etiology of affective disorders. However, genetic studies have produced conflicting results concerning an association of 5-HTT with bipolar disorder. We examined a variable number tandem repeat in the regulatory region of this gene to investigate the possible contribution of 5-HTT to bipolar disorder susceptibility in a 22-pedigree series. By affected-sib-pair analysis and the transmission/disequilibrium test, we found no significant linkage or association of 5-HTT to bipolar disorder. During the course of this study, we adapted a PCR technique designed to amplify long templates to replicating long GC stretches with complex structure. We also refined the location of 5-HTT by radiation hybrid mapping, placing the locus between D17S1294 and SHGC11022 on 17q11.2.

Alleles↗
PubMed1998

Kainate and AMPA receptor binding in seizure-prone and seizure-resistant inbred mouse strains.

Glutamate and its receptors represent the major excitatory neurotransmission system in the mammalian brain and are considered important in the pathogenesis of many neurological diseases. The present study describes saturation binding experiments performed to measure the affinity (Kd) and density (Bmax) of kainate and AMPA receptors in striatum, cortex and hippocampus from mature DBA/2J (DBA) and C57BL/6J (C57) mice. Previous studies have documented that these two strains differ significantly in seizure susceptibility, with DBA mice exhibiting greater sensitivity in various convulsant tests compared to C57 mice. Non-linear regression analysis of binding data together with Student's t-test and ANOVA revealed significantly higher densities of kainate receptors in striatum and of AMPA receptors in cortex of DBA mice. C57 mice exhibited higher striatal [3H]AMPA binding. There were no significant differences between the mouse strains in binding sites prepared from hippocampus and no differences in affinity for either receptor in any brain region studied. The results support a role for kainate and AMPA receptors in seizure sensitivity, possibly by influencing glutamate transmission in specific pathways. It is unlikely, however, that these receptors account for the generation of seizures alone but rather cooperate with other glutamatergic and non-glutamatergic neurotransmitter systems.

Animals↗
PubMed1998

Genotyping microsatellite polymorphisms by agarose gel electrophoresis with ethidium bromide staining: application to quantitative trait loci analysis of seizure susceptibility in mice.

Agarose gel electrophoresis with ethidium bromide staining (AGE/EBS) is an efficient and reliable method for analyzing microsatellite polymorphisms. We report the use of AGE/EBS for analyzing DNA microsatellite polymorphisms in a preliminary quantitative trait loci (QTL) study of seizure susceptibility in which a candidate gene strategy was used to direct initial mapping efforts. F2 intercross progeny, derived from seizure-sensitive DBA/2J (D2) and seizure-resistant C57BL/6J (B6) inbred strains of mice, were tested for their sensitivity to the seizure-inducing effect of pentylenetetrazol (PTZ), a gamma-aminobutyric acid (GABA) receptor antagonist. A semi-automated method is described, in which DNA microsatellites were amplified by polymerase chain reaction (PCR) to yield products of 100-200 base pair (bp) in length. Alleles were separated on 3-6% MetaPhor agarose gels, stained with ethidium bromide, and visualized by ultraviolet (UV) illumination. Univariate analysis of genotype and phenotype data provides evidence for a seizure-related QTL on chromosome 5, near genes coding for the GABAA receptor subunits alpha 5 and gamma 3. Interestingly, this suggestive QTL derives from the more resistant B6 strain, but it nonetheless provides impetus for the characterization of possible strain differences in these two candidate genes. Overall, these results demonstrate that AGE/EBS can be useful for rapid screening of genomic regions of special interest in QTL mapping studies.

Animals↗
PubMed1998

Human G(olf) gene polymorphisms and vulnerability to bipolar disorder.

Two intronic polymorphisms of the human alpha subunit of the olfactory G-protein (G(olf)) are described. They were detected with single-stranded conformational polymorphism (SSCP) methods and confirmed by sequencing both strands. These single base pair (bp) substitutions occur in introns 3 (an A/G at 35 bp 3' from the exon 3/intron 3 5' splice site) and 10 (an T/G at 7 bp 5' from the 3' splice site). Both polymorphisms are relatively common, with minor allele frequencies of 31% (intron 3) and 16% (intron 10). The intron 3 variant shows no linkage disequilibrium with an intron 5 (CA)n microsatellite located approximately 50 kb 3' from the intron 3 variant, among a small group of German individuals with schizophrenia. The intron 3 variant is interesting because it may create an 'in-frame' cryptic splice site which, if activated, would add 12 residues to exon 3. The intron 10 variant is interesting because a purine is substituted for a pyrimidine in the 'polypyrimidine' tract of the 3' splice site, a single base substitution of the type which has been associated with aberrant splicing in the androgen receptor gene.

Alleles↗