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Biomedical subjects

W H Berrettini

Publications and source records attributed to W H Berrettini.

At least 19 recordsLinked to original sources
PubMed2006

Association of OPRM1 A118G variant with the relative reinforcing value of nicotine.

RATIONALE: The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement. METHODS: In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence. RESULTS: The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups. CONCLUSIONS: This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women.

Adaptation, Psychological↗
PubMed2005

Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder.

Recent studies have indicated that the brain-derived neurotrophic factor (BDNF) gene is involved in the etiology of bipolar disorder (BPD). Two family-based association studies showed that the Val allele of the functional polymorphism Val66Met in the BDNF gene is associated with BPD; however, others could not confirm the results. Here we performed a replication study in an independent sample and tested the hypothesis that the Val66 allele in the BDNF gene confers susceptibility to bipolar I disorder (BPI). Six hundred twenty-one patients with BPI and 998 control subjects were genotyped for the Val66Met polymorphism. All cases and controls were of European descent. All BPI patients had a positive family history of affective disorder. The frequency of the Val allele was significantly increased in BPI patient when compared to controls (chi2 = 4.8; df = 1; P = 0.028; two-sided; OR = 1.22; 95% CI: 1.02-1.47). Results confirm previous findings and suggest that the Val allele increases risk for BPI in patients of European descent. Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.

Adult↗
PubMed2005

Alternative transcripts and evidence of imprinting of GNAL on 18p11.2.

Genetic studies implicating the region of human chromosome 18p11.2 in susceptibility to bipolar disorder and schizophrenia have observed parent-of-origin effects that may be explained by genomic imprinting. We have identified a transcriptional variant of the GNAL gene in this region, employing an alternative first exon that is 5' to the originally identified start site. This alternative GNAL transcript encodes a longer functional variant of the stimulatory G-protein alpha subunit, Golf. The isoforms of Golf display different expression patterns in the CNS and functionally couple to the dopamine D1 receptor when heterologously expressed in Sf9 cells. In addition, there are CpG islands in the vicinity of both first exons that are differentially methylated, a hallmark of genomic imprinting. These results suggest that GNAL, and possibly other genes in the region, is subject to epigenetic regulation and strengthen the case for a susceptibility gene in this region.

Alternative Splicing↗
PubMed2004

Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility.

PURPOSE: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. METHODS: We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n = 407) and unrelated controls (n = 284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n = 153), childhood absence (n = 84), juvenile myoclonic (n = 111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n = 59) and all were of European ancestry. RESULTS: SNP rs#1130183 (C > T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square = 5.65, d.f. = 1, P = 0.017, odds ratio 0.52, 95% CI 0.33-0.82. CONCLUSION: The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.

Chi-Square Distribution↗
PubMed2004

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial.

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

Administration, Cutaneous↗
PubMed2003

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.

Anorexia Nervosa↗
PubMed2003

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset.

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.

Animals↗
PubMed2002

Evidence for a susceptibility gene for anorexia nervosa on chromosome 1.

Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n=37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.

Adult↗
PubMed2001

Quantitative genetic study of maximal electroshock seizure threshold in mice: evidence for a major seizure susceptibility locus on distal chromosome 1.

We conducted a quantitative trait locus (QTL) mapping study to dissect the multifactorial nature of maximal electroshock seizure threshold (MEST) in C57BL/6 (B6) and DBA/2 (D2) mice. MEST determination involved a standard paradigm in which 8- to 12-week-old mice received one shock per day with a daily incremental increase in electrical current until a maximal seizure (tonic hindlimb extension) was induced. Mean MEST values in parental strains were separated by over five standard deviation units, with D2 mice showing lower values than B6 mice. The distribution of MEST values in B6xD2 F2 intercrossed mice spanned the entire phenotypic range defined by parental strains. Statistical mapping yielded significant evidence for QTLs on chromosomes 1, 2, 5, and 15, which together explained over 60% of the phenotypic variance in the model. The chromosome 1 QTL represents a locus of major effect, accounting for about one-third of the genetic variance. Experiments involving a congenic strain (B6.D2-Mtv7(a)/Ty) enabled more precise mapping of the chromosome 1 QTL and indicate that it lies in the genetic interval between markers D1Mit145 and D1Mit17. These results support the hypothesis that the distal portion of chromosome 1 harbors a gene(s) that has a fundamental role in regulating seizure susceptibility.

Animals↗
PubMed2001

Acute cocaine-induced seizures: differential sensitivity of six inbred mouse strains.

Mature male and female mice from six inbred stains were tested for susceptibility to behavioral seizures induced by a single injection of cocaine. Cocaine was injected ip over a range of doses (50-100 mg/kg) and behavior was monitored for 20 minutes. Seizure end points included latency to forelimb or hindlimb clonus, latency to clonic running seizure and latency to jumping bouncing seizure. A range of strain specific sensitivities was documented with A/J and SJL mice being most sensitive and C57BL/6J most resistant. DBA/2J, BALB/cByJ and NZW/LacJ strains exhibited intermediate sensitivity. EEG recordings were made in SJL, A/J and C57BL/6J mice revealing a close correspondence between electrical activity and behavior. Additionally, levels of cocaine determined in hippocampus and cortex were not different between sensitive and resistant strains. Additional studies of these murine strains may be useful for investigating genetic influences on cocaine-induced seizures.

Animals↗
PubMed2001

Molecular linkage studies of bipolar disorders.

OBJECTIVES: To review the reports of linkage findings for bipolar disorder. METHODS: Literature review of published linkage findings in bipolar disorder. RESULTS: There are several regions of the human genome that have been implicated repeatedly by independent investigators. These include 4p16, 12q24, 18q22, 18p11, 21q21 and 22q11. Two of these regions (18p11 and 22q11) are also implicated in genome scans of schizophrenia, suggesting that these two distinct nosological categories may share some genetic susceptibility. This hypothesis can only be tested when the underlying genes are identified.

Bipolar Disorder↗
PubMed2001

Lack of association between an interleukin 1 beta (IL-1beta) gene variation and refractory temporal lobe epilepsy.

PURPOSE: We attempted to confirm recent findings of Kanemoto et al. that demonstrated a positive association (p < 0.017) between a polymorphism in the promoter region of the interleukin 1-beta (IL-1beta) gene and the clinical phenotype of temporal lobe epilepsy with hippocampal sclerosis (TLE+HS). METHODS: We determined the frequency of this polymorphism in a group of 61 TLE+HS patients of European ancestry and compared it with that found in 119 ethnically matched control subjects. RESULTS: Analysis of genotype and allele frequencies showed no statistically significant difference in the distribution of the polymorphism between the two groups (p = 0.10). CONCLUSIONS: These data suggest that this IL-1beta promoter polymorphism does not act as a strong susceptibility factor for TLE+HS in a population of individuals of European ancestry.

Epilepsy, Temporal Lobe↗
PubMed2001

Effects of strain, behavior and age on the self-administration of ethanol, nicotine, cocaine and morphine by two rat strains.

Two genetically different strains, Brown Norway rats (BNR) and Wistar Kyoto rats (WKR), with the latter showing higher emotionality and lower plasma stress catecholamine responses, were compared for their voluntary intake of ethanol, nicotine, cocaine and morphine. Younger BNR self-administered the same amounts of all 4 substances as did the younger WKR suggesting a similar genetic basis for all drugs at this age. Older BNR consumed less ethanol and nicotine but equal amounts of cocaine and morphine as compared to older WKR, and older BNR were more sensitive to the effects of ethanol than WKR suggesting a different genetic basis for different drugs at an older age. Forcing both strains to consume one of the drugs did not affect a subsequent voluntary consumption of ethanol and morphine but reduced nicotine intake in WKR and decreased cocaine intake in both strains suggesting that drug use is determined by individual preferences and not drug exposure per se. The behavioral characteristics of both strains coincide only with the self-administration of ethanol and nicotine supporting a possible genetic linkage between anxiety/stress and ethanol and nicotine use.

Administration, Oral↗
PubMed2001

C18orf2, a novel, highly conserved intronless gene within intron 5 of the GNAL gene on chromosome 18p11.

We have characterized a novel intronless human gene (C18orf2) which is embedded in intron 5 of the G-protein gene (GNAL) on chromosome 18p11. This gene codes for a 199 amino acid polypeptide with a predicted molecular weight of 22.1 kDa. It is highly homologous to a number of predicted developmental proteins in organisms ranging from yeasts to Drosophila. C18orf2 mRNA was found to be expressed in various tissues.

Amino Acid Sequence↗
PubMed2000

Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence.

To analyze candidate genes and establish complex genotype-phenotype relationships against a background of high natural genome sequence variability, we have developed approaches to (i) compare candidate gene sequence information in multiple individuals; (ii) predict haplotypes from numerous variants; and (iii) classify haplotypes and identify specific sequence variants, or combinations of variants (pattern), associated with the phenotype. Using the human mu opioid receptor gene (OPRM1) as a model system, we have combined these approaches to test a potential role of OPRM1 in substance (heroin/cocaine) dependence. All known functionally relevant regions of this prime candidate gene were analyzed by multiplex sequence comparison in 250 cases and controls; 43 variants were identified and 52 different haplotypes predicted in the subgroup of 172 African-Americans. These haplotypes were classified by similarity clustering into two functionally related categories, one of which was significantly more frequent in substance-dependent individuals. Common to this category was a characteristic pattern of sequence variants [-1793T-->A, -1699Tins, -1320A-->G, -111C-->T, +17C-->T (A6V)], which was associated with substance dependence. This study provides an example of approaches that have been successfully applied to the establishment of complex genotype-phenotype relationships in the presence of abundant DNA sequence variation.

Adult↗
PubMed2000

Are schizophrenic and bipolar disorders related? A review of family and molecular studies.

Schizophrenic and bipolar disorders are similar in several epidemiologic respects, including age at onset, lifetime risk, course of illness, worldwide distribution, risk for suicide, gender influence (men and women at equal risk for both groups of disorders), and genetic susceptibility. Despite these similarities, schizophrenia and bipolar disorders are typically considered to be separate entities, with distinguishing clinical characteristics, non-overlapping etiologies, and distinct treatment regimens. Over the past three decades, multiple family studies are consistent with greater nosologic overlap than previously acknowledged. Molecular linkage studies (conducted during the 1990s) reveal that some susceptibility loci may be common to both nosologic classes. This indicates that our nosology will require substantial revision during the next decade, to reflect this shared genetic susceptibility, as specific genes are identified.

Bipolar Disorder↗
PubMed2000

A search for susceptibility loci for anorexia nervosa: methods and sample description.

BACKGROUND: Eating disorders have not traditionally been viewed as heritable illnesses; however, recent family and twin studies lend credence to the potential role of genetic transmission. The Price Foundation funded an international, multisite study to identify genetic factors contributing to the pathogenesis of anorexia nervosa (AN) by recruiting affective relative pairs. This article is an overview of study methods and the clinical characteristics of the sample. METHODS: All probands met modified DSM-IV criteria for AN; all affected first, second, and third degree relatives met DSM-IV criteria for AN, bulimia nervosa (BN), or eating disorder not otherwise specified (NOS). Probands and affected relatives were assessed diagnostically with the Structured Interview for Anorexia and Bulimia. DNA was collected from probands, affected relatives and a subset of their biological parents. RESULTS: Assessments were obtained from 196 probands and 237 affected relatives, over 98% of whom are of Caucasian ancestry. Overall, there were 229 relative pairs who were informative for linkage analysis. Of the proband-relative pairs, 63% were AN-AN, 20% were AN-BN, and 16% were AN-NOS. For family-based association analyses, DNA has been collected from both biological parents of 159 eating-disordered subjects. Few significant differences in demographic characteristics were found between proband and relative groups. CONCLUSIONS: The present study represents the first large-scale molecular genetic investigation of AN. Our successful recruitment of over 500 subjects, consisting of affected probands, affected relatives, and their biological parents, will provide the basis to investigate genetic transmission of eating disorders via a genome scan and assessment of candidate genes.

Adult↗