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Biomedical subjects

P F Sullivan

Publications and source records attributed to P F Sullivan.

At least 19 recordsLinked to original sources
PubMed2006

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample.

Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003<Fisher's exact P<0.001), and the most significant single marker, rs7254880, tags an associated haplotype with frequency 0.071 in cases compared to 0.034 in controls (chi2 15.563, P<0.00008, 5000 permutation P<0.001, OR 2.17); inclusion of affected siblings gives similar results. Expression analyses conducted in independent postmortem brain samples show that expression of ZNF699 mRNA is significantly reduced in the dorsolateral prefrontal cortex of individuals carrying this haplotype compared with other observed haplotype combinations.

Alcohol-Related Disorders↗
PubMed2006

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4.

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50-60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 x 10(-6), at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0-2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

Aged↗
PubMed2005

Is Swedish snus associated with smoking initiation or smoking cessation?

Nicotine replacement therapies (NRT) are an effective treatment for tobacco dependence, yet most smokers do not quit or remain abstinent. We investigated whether Swedish snus (snuff) use was associated with smoking cessation among males participating in a large population based twin study in Sweden. Snus use was associated with smoking cessation but not initiation. Given that snus delivers comparable nicotine concentrations but carries lesser cancer risk than cigarettes, snus may be a widely used, non-medical form of NRT. Evaluation of the efficacy of snus for smoking cessation should be evaluated in randomised clinical trials.

Adult↗
PubMed2004

The nosology of sub-acute and chronic fatigue syndromes that follow infectious mononucleosis.

BACKGROUND: A previous principal components analysis of symptoms occurring after infectious mononucleosis suggested that a discrete fatigue syndrome occurs, which is independent of psychiatric disorder. This work has not been replicated and no latent class analysis of subjects has been published. METHOD: We prospectively examined a cohort of 150 American primary care patients 2 and 6 months after the onset of corroborated infectious mononucleosis. A subset of 50 subjects was studied 4 years after onset. We performed principal components analyses of both psychological and somatic symptoms and latent class analyses of subjects. RESULTS: Principal components analyses consistently delineated two fatigue factors at 2 and 6 months and one fatigue factor at 4 years. These factors were separate from a mixed anxiety and depressive factor. A four-class solution for the latent class analyses consisted of most subjects with few symptoms, a few with many symptoms, a group with predominantly mood symptoms and some subjects with fatigue symptoms. CONCLUSIONS: The symptoms of the principal factors with fatigue were similar to those previously described. Both the factors and classes were independent of an equally delineated mood factor and class. These results support the existence of two discrete chronic fatigue syndromes after infectious mononucleosis, one of which is still demonstrable 4 years after onset.

Acute Disease↗
PubMed2003

Fatigue in a community sample of twins.

BACKGROUND: Fatigue is a complex symptom associated with many physiological, psychological and pathological processes. Its correlates and typology remain inadequately understood. METHOD: These data were from two large, longitudinal twin studies. Trained interviewers enquired as to the presence of a > or = 5 day period in the previous year of fatigue or tiredness that interfered with daily activities. A range of potential correlates was assessed in a structured interview: demography; health beliefs; the presence of nine physical disorders; mood, anxiety and addictive disorders; neuroticism and extraversion; recollections of parental rearing; and nine stressful life events. Statistical analyses included logistic regression, CART, MARS, latent class analysis and univariate twin modelling. RESULTS: Data were available for interfering fatigue (IF) on 7740 individual twins (prevalence 9.9% in the previous year). IF was significantly associated with 42 of 52 correlates (most strongly with major depression, generalized anxiety disorder, reported major health problems and neuroticism). Multivariate analyses demonstrated that IF is a highly complex construct with different sets of correlates in its subtypes. There were two broad clusters of correlates of IF: (a) major depression, generalized anxiety disorder and neuroticism; and (b) beliefs of ill health coexisting with alcoholism and stressful life events. Twin analyses were consistent with aetiological heterogeneity--genetic effects may be particularly important in women and shared environmental effects in men. CONCLUSIONS: IF is a complex and common human symptom that is highly heterogeneous. More precise understanding of the determinants of IF may lead to a fuller understanding of more extreme conditions like chronic fatigue syndrome.

Adult↗
PubMed2003

Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

Carrier Proteins↗
PubMed2003

Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput.

The large number of single nucleotide polymorphism (SNP) markers available in the public databases makes studies of association and fine mapping of disease loci very practical. To provide information for researchers who do not follow SNP genotyping technologies but need to use them for their research, we review here recent developments in the fields. We start with a general description of SNP typing protocols and follow this with a summary of current methods for each step of the protocol and point out the unique features and weaknesses of these techniques as well as comparing the cost and throughput structures of the technologies. Finally, we describe some popular techniques and the applications that are suitable for these techniques.

Alleles↗
PubMed2002

Latent class analysis of symptoms associated with chronic fatigue syndrome and fibromyalgia.

BACKGROUND: Chronic fatigue syndrome and fibromyalgia continue to be perplexing conditions of unknown validity. Aetiological and symptomatic heterogeneity is likely and the distinctiveness of these disorders remains unclear. Our aims were to investigate empirically symptomatic heterogeneity in chronic fatigue syndrome and fibromyalgia. METHODS: Latent class analysis was applied to data from 646 patients who met accepted criteria for chronic fatigue syndrome and/or fibromyalgia who were systematically evaluated at a specialist fatigue clinic. Thirty-two symptoms commonly found in chronic fatigue syndrome and fibromyalgia were entered into the latent class analysis. RESULTS: We chose to interpret a four class solution. The classes appeared to differ in a graded fashion (rather than qualitatively) for symptom endorsements, pre-morbid characteristics, and co-morbidity with panic disorder and major depression. CONCLUSIONS: These results were unexpected given the usual assumption of the distinctiveness of chronic fatigue syndrome and fibromyalgia. These results support a conceptualization of chronic fatigue syndrome and fibromyalgia as being characterized by greater similarities than differences.

Adult↗
PubMed2001

Association of the tryptophan hydroxylase gene with smoking initiation but not progression to nicotine dependence.

We investigated the association between two markers in the seventh intron of the tryptophan hydroxylase gene (TPH C218A and C779A) in a population-based case control study of 780 genotyped subjects. As in prior studies, the two markers were in strong linkage disequilibrium. The phenotypes we studied were smoking initiation and progression to nicotine dependence. Allele, genotype, and estimated haplotype frequencies for each marker were highly significantly different for smoking initiation (P < 0.0004 for each comparison) and were nonsignificant for progression to nicotine dependence. An empirical test suggested that the positive results were unlikely to have resulted from population stratification. Our results are similar to those of Lerman et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:000-000] in associating these TPH markers with a construct related to smoking initiation but dissimilar in the variable implicated. If these results replicate in other samples, the serotonergic system may be involved in the etiology of smoking initiation given the rate-limiting role of TPH in the biosynthesis of serotonin.

Alleles↗
PubMed2001

An association study of DRD5 with smoking initiation and progression to nicotine dependence.

A large body of genetic epidemiological data strongly implicate genetic factors in the etiology of smoking behavior. Polymorphisms of genes in the dopaminergic system are plausible functional candidate genes and a linkage and an association study suggested that the type 5 dopamine receptor gene (DRD5) may be etiologically involved. We investigated the association of four DRD5 polymorphisms with smoking initiation and progression to nicotine dependence in a population-based sample of over 900 subjects. For smoking initiation, there was no significant association with the four DRD5 markers we studied; however, maximum likelihood analyses suggested the presence of a haplotype protective against smoking initiation. For progression to nicotine dependence, there were no strongly significant associations with the four DRD5 markers or for the estimated haplotypes. These data are not consistent with a strong etiological role for DRD5 in the etiology of these complex smoking behaviors.

Adolescent↗
PubMed2001

Analysis of epistasis in linked regions in the Irish study of high-density schizophrenia families.

Epistasis may be important in the etiology of schizophrenia. Analysis of epistasis has been important in the positional cloning of a gene involved in the etiology of type II diabetes mellitus. We investigated the importance of epistasis among six linked regions in 268 multiplex pedigrees in the Irish Study of High-Density Schizophrenia Families (ISHDSF) by computing pairwise correlations between nonparametric linkage scores for narrow, intermediate, and broad diagnostic definitions. The linked regions were on chromosomes 2, 4, 5, 6, 8, and 10. No correlation reached our a priori level of statistical significance. Using this statistical approach, we did not find evidence of important epistatic effects among these six regions in the ISHDSF.

Chromosomes, Human↗
PubMed2001

Genetic case-control association studies in neuropsychiatry.

Case-control association studies use genetic markers as putative etiologic risk factors. The approach is controversial and has tended to produce associations in neuropsychiatry that do not stand the test of time. We studied the processes that can bias the outcomes away from a true representation of the relationship between a genetic marker and a neuropsychiatric disorder. If conducted with care and mindfulness of the potential pitfalls, case-control association studies can be an important tool for psychiatric genetic research.

Brain↗
PubMed2001

A randomized controlled trial of motivational enhancement therapy (MET) for mild to moderate alcohol dependence.

OBJECTIVE: This study was designed to conduct a randomized controlled trial of motivational enhancement therapy (MET) with two control conditions: nondirective reflective listening (NDRL) and no further counseling (NFC); and to conduct this study in a sample of patients with a primary diagnosis of mild to moderate alcohol dependence, in a "real-life" clinical setting. METHOD: Patients with mild to moderate alcohol dependence were recruited, assessed and treated at the Community Alcohol and Drug Service of Christchurch, New Zealand. All patients received a feedback/education session before randomization to either four sessions of MET, four sessions of NDRL, or NFC. Outcome data on 122 subjects (57.4% men) were obtained 6 months following the end of treatment, by an interviewer who was blind to the treatment condition. The primary drinking outcome was unequivocal heavy drinking, defined as drinking 10 or more standard drinks six or more times in the follow-up period. Global assessment scale (GAS) measured general personal/social functioning. RESULTS: Of patients treated with MET, 42.9% showed unequivocal heavy drinking compared with 62.5% of the NDRL and 65.0% of the NFC groups (p = .04). No significant differences were found for GAS score according to treatment condition. CONCLUSIONS: In patients with mild to moderate alcohol dependence, MET is more effective for reducing unequivocal heavy drinking than either a feedback/education session alone or four sessions of NDRL. MET can be considered an effective "value added" counseling intervention in a real-life clinical setting. In patients with mild to moderate alcohol dependence, nondirective reflective listening provides no additional advantage over a feedback/education session alone.

Adolescent↗
PubMed2000

Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor beta2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence.

Several types of evidence, including experiments with mice that lack the nicotinic acetylcholine receptor beta2-subunit gene (CHRNB2), have suggested that a beta2-containing nicotinic receptor is necessary for at least some of the reinforcing properties of nicotine. However, sequence variations in CHRNB2 have not been reported, and its role in influencing human smoking behavior and nicotine dependence is not known. We screened most of the introns and exons and found five novel single nucleotide polymorphisms (SNPs). We tested four of these SNPs in three large, carefully selected samples: nonsmokers (n = 317) and regular smokers low levels of nicotine dependence (ND, n = 238), or smokers with high-ND (n = 317). None of the four polymorphisms we tested, nor their estimated haplotypes, were associated with smoking initiation or progression to nicotine dependence.

DNA↗
PubMed2000

Twin studies of eating disorders: a review.

OBJECTIVE: Twin methodology has been used to delineate etiological factors in many medical disorders and behavioral traits including eating disorders. Although twin studies are powerful tools, their methodology can be arcane and their implications easily misinterpreted. METHOD: The goals of this study are to (a) review the theoretical rationale for twin studies; (b) provide a framework for their interpretation and evaluation; (c) review extant twin studies on eating disorders; and (d) explore the implications for understanding etiological issues in eating disorders. DISCUSSION: On the basis of this review, it is not possible to draw firm conclusions regarding the precise contribution of genetic and environmental factors to anorexia nervosa. Twin studies confirm that bulimia nervosa is familial and reveal significant contributions of additive genetic effects and of unique environmental factors in liability to bulimia nervosa. The magnitude of the contribution of shared environment is less clear, but in the studies with the greatest statistical power, it appears to be less prominent than additive genetic factors.

Anorexia Nervosa↗
PubMed2000

Outcome of anorexia nervosa: eating attitudes, personality, and parental bonding.

BACKGROUND: We examined eating attitudes, personality, and parental bonding in women with a history of anorexia nervosa stratified by degree of recovery in comparison to randomly selected controls. We were interested in the distinguishing characteristics of recovery and of chronic anorexia nervosa. METHOD: All female new referrals to an eating disorders service between January 1, 1981 and December 31, 1984 with probable or definite anorexia nervosa were eligible for inclusion. 86.4% of these women ("cases") were located and agreed to participate. The control group was a random community sample. All subjects were interviewed with a structured diagnostic instrument and completed a battery of psychological inventories including the Eating Disorder Inventory (EDI), the Three-Factor Eating Questionnaire (TFEQ), the Temperament and Character Inventory (TCI), and the Parental Bonding Instrument (PBI). RESULTS: We divided the anorexia follow-up sample into full recovery (n = 21), partial recovery (n = 34), and chronically ill (n = 15) and compared them to community controls (n = 98). The chronically ill group was distinguished by a lower desired body mass index (BMI), higher cognitive restraint on the TFEQ, higher Drive for Thinness and Bulimia on the EDI, lower maternal and paternal care on the PBI, and high harm avoidance and low self-directedness on the TCI. The full recovery group scored high on self-directedness and cooperativeness on the TCI. CONCLUSIONS: The domains of personality, character, and parental bonding differ among categories of recovery in anorexia nervosa. Whether these differences contribute to recovery or emerge during recovery or lack thereof remains an unanswered question.

Adult↗
PubMed2000

The relation between risk factors for binge eating and bulimia nervosa: a population-based female twin study.

This study investigated the differential risk factors for the initiation of binge eating and the transition from binge eating to bulimia nervosa. Women from a population-based twin registry (850 complete pairs) were assessed with respect to specific measured variables (including demographics, religiosity, lifetime psychopathology, current symptomatology, and personality) and latent genetic and environmental variables. Because of the relative rarity of bulimia nervosa, statistical power was low, but findings suggested considerable overlap between the genetic risk factors for the development of binge eating and the genetic risk factors for the transition from binge eating to bulimia nervosa. Genetic risk factors for binge eating and bulimia nervosa may be largely similar, whereas nonshared environment may be important in influencing the risk for bulimia nervosa once binge eating is initiated.

Adult↗