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Biomedical subjects

Patrick F Sullivan

Publications and source records attributed to Patrick F Sullivan.

At least 55 records · Page 3Linked to original sources
PubMed2004

Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics.

Many smoking-related phenotypes are substantially heritable. One genome scan of nicotine dependence (ND) has been published and several others are in progress and should be completed in the next 5 years. The goal of this hypothesis-generating study was two-fold. First, we present further analyses of our genome scan data for ND published by Straub et al. [1999: Mol Psychiatry 4:129-144] (PMID: 10208445). Second, we used the method described by Cox et al. [1999: Nat Genet 21:213-215] (PMID: 9988276) to search for epistatic loci across the markers used in the genome scan. The overall results of the genome scan nearly reached the rigorous Lander and Kruglyak [1995: Nat Genet 11:241-247] criteria for "significant" linkage with the best findings on chromosomes 10 and 2. We then looked for correspondence between genes located in the 10 regions implicated in affected sibling pair (ASP) and epistatic linkage analyses with a list of genes suggested by microarray studies of experimental nicotine exposure and candidate genes from the literature. We found correspondence between linkage and microarray/candidate gene studies for genes involved with the mitogen-activated protein kinase (MAPK) signaling system, nuclear factor kappa B (NFKB) complex, neuropeptide Y (NPY) neurotransmission, a nicotinic receptor subunit (CHRNA2), the vesicular monoamine transporter (SLC18A2), genes in pathways implicated in human anxiety (HTR7, TDO2, and the endozepine-related protein precursor, DKFZP434A2417), and the micro 1-opioid receptor (OPRM1). Although the hypotheses resulting from these linkage and bioinformatic analyses are plausible and intriguing, their ultimate worth depends on replication in additional linkage samples and in future experimental studies.

Chromosome Mapping↗
PubMed2004

A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence.

BACKGROUND: Numerous twin studies have reported significant genetic contributions to the variability of tobacco initiation (TI), while fewer studies have shown similar results for the persistence of smoking behavior, or nicotine dependence (ND). As the development of ND requires regular tobacco use (RTU) which in turn requires TI, a conditional approach is necessary. METHOD: We used structural equation modeling of multi-step conditional processes to examine the relationship between genetic and environmental risk factors for TI, RTU and ND. The tobacco variables were assessed by personal interview in female, male and opposite-sex twin pairs from the population-based Virginia Twin Registry. RESULTS: The results suggested that the liabilities to TI, RTU and ND were correlated. Over 80 % of the variance in liability to TI and RTU were shared, and a smaller proportion was shared between RTU and ND. The heritabilities were estimated at 75 %, 80 % and 60 % respectively for TI, RTU and ND. The variance specific to liability to RTU was entirely accounted for by additive genetic factors. Only a modest part of the heritability in liability of ND was due to genetic factors specific to ND. Shared environmental factors were not significant. No sex differences were found for the sources of variation or causal paths, but prevalences were significantly greater in males versus females. CONCLUSIONS: This study showed significant overlap in the contribution of genetic factors to individual differences in TI, RTU and ND. Furthermore, there was evidence for significant additional genetic factors specific to RTU and ND.

Adult↗
PubMed2004

Psychiatric and medical symptoms in binge eating in the absence of compensatory behaviors.

OBJECTIVE: To explore the extent to which binge eating in the absence of compensatory behaviors (BE) is associated with psychiatric and medical symptoms in men and women and to control for the independent effects of BMI. RESEARCH METHODS AND PROCEDURES: A series of regression models was applied to questionnaire data on 8045 twins, 18 to 31 years old, from a population-based Norwegian registry. RESULTS: BE was significantly associated with elevated obesity, overweight, symptoms of eating disorders, symptoms of anxiety and depression, panic attacks, depressive episodes, and reduced life satisfaction in both men and women. In women, BE was independently associated with insomnia and early menarche. In men, BE was independently associated with specific phobia, daily smoking, alcohol use, use of pain medication, impairment due to mental health, neck-shoulder, lower back, and chronic muscular pain, and impairment due to physical health. Both men and women with BE reported higher rates of psychiatric treatment. DISCUSSION: Our results indicate that there is substantial comorbidity between BE and psychiatric symptoms independently of BMI for both men and women. Medical symptoms co-occur less frequently than previously reported from treatment-seeking populations in women. Across all domains, the array of symptoms exhibited by men with BE was broader than that observed in women with BE. This observation suggests the importance of considering gender differences in future studies of psychiatric and medical morbidity, binge eating, and obesity.

Adult↗
PubMed2004

Bipolar II disorder: personality and outcome in two clinical samples.

OBJECTIVE: To compare the personality traits and disorders of patients with bipolar II disorder and major depression and to examine the impact on treatment outcome of a bipolar II diagnosis. METHOD: Patients from two clinical trials, a depressive sample (n = 195, 10% bipolar II) and a bulimic sample (n = 135, 16% bipolar II), were assessed for personality traits using DSM-IV criteria. Patients were randomised to treatments (fluoxetine or nortriptyline for depressive sample; cognitive behaviour therapy for bulimic sample) and followed for 3 years (depressive sample) or 5 years (bulimic sample) to assess the impact on outcome of a bipolar II diagnosis. RESULTS: Bipolar II patients were assessed as having more borderline, histrionic and schizotypal personality traits than patients with major depression. A baseline bipolar II diagnosis did not impact negatively on treatment outcome, and less than 5% of bipolar II patients developed bipolar I disorder during follow up. CONCLUSIONS: The low rate of conversion of bipolar II to bipolar I disorder and the lack of adverse impact of the diagnosis on outcome, questions the need for antimanic or mood stabiliser medication in most bipolar II patients.

Adrenergic Uptake Inhibitors↗
PubMed2004

Evaluation of genetic substructure in the Irish Study of High-Density Schizophrenia Families.

The presence of genetic substructure has the potential to diminish the chances of detecting a linkage signal. Using a Markov chain Monte Carlo procedure developed by Pritchard and colleagues and implemented in the program STRUCTURE, we evaluated the evidence for genetic substructure using genotypes from 37 microsatellite markers in affected individuals selected at random from 263 multiplex families in the Irish Study of High-Density Schizophrenia Families. We found no evidence for the presence of genetic substructure in this sample.

Family↗
PubMed2004

Genotyping accuracy for whole-genome amplification of DNA from buccal epithelial cells.

We compared the accuracy of genotyping for DNA extracted from lymphocytes to that of DNA amplified from buccal epithelial cells. Amplification was via a rolling circle/phi29 DNA polymerase commercial kit. Paired buccal and lymphocyte DNA samples were available from 30 individuals. All samples were genotyped for 12 SNPs, 5 microsatellites and 2 VNTRs. The accuracy of genotyping (no-call proportions, reproducibility, and concordance) was similar for DNA from lymphocytes in comparison to amplified DNA from buccal samples. If used with caution, these data suggest that rolling-circle whole-genome amplification can be used to increase the DNA mass available for large-scale genotyping projects based on DNA from buccal cells.

DNA↗
PubMed2003

Multipoint and single point non-parametric linkage analysis with imperfect data.

We used simulation to explore the impact of common data imperfections (i.e., missing parents, genotyping error, map error, and missing genotypes) upon the performance of multipoint and single point linkage analysis in the analyses of linkage data from pairs of siblings affected with an idealized complex trait. The performance of single point and multipoint linkage was similar under an unrealistic best case scenario; however, when four data imperfections were combined, the performance of single point linkage analysis appeared to be superior to multipoint. The absence of parental genotypes in the presence of 1% genotype error led to marked degradation of linkage signal, particularly for multipoint analyses.

Computer Simulation↗
PubMed2003

Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.

CONTEXT: There are many published twin studies of schizophrenia. Although these studies have been reviewed previously, to our knowledge, no review has provided quantitative summary estimates of the impact of genes and environment on liability to schizophrenia that also accounted for the different ascertainment strategies used. OBJECTIVE: To calculate meta-analytic estimates of heritability in liability and shared and individual-specific environmental effects from the pooled twin data. DATA SOURCES: We used a structured literature search to identify all published twin studies of schizophrenia, including MEDLINE, dissertation, and books-in-print searches. STUDY SELECTION: Of the 14 identified studies, 12 met the minimal inclusion criteria of systematic ascertainment. DATA SYNTHESIS: By using a multigroup twin model, we found evidence for substantial additive genetic effects-the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia-joint estimate, 11% (95% confidence interval, 3%-19%). CONCLUSIONS: Despite evidence of heterogeneity across studies, these meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences. These results are broadly informative in that they provide no information about the specific identity of these etiological influences, but they do provide a component of a unifying empirical basis supporting the rationality of searches for underlying genetic and common environmental etiological factors.

Diseases in Twins↗
PubMed2003

Causes and recovery in anorexia nervosa: the patient's perspective.

OBJECTIVE: We explored anorexic patients' subjective accounts of the causes of their anorexia and of the factors that fostered recovery. Subjective accounts could assist in understanding this complicated and often intractable disorder. METHOD: All female new referrals to an eating disorders service underwent extensive interviews including open-ended questions about their beliefs concerning the causes of their anorexia nervosa and factors that led to recovery. Responses were categorized by two independent raters. RESULTS: The most commonly mentioned perceived causes were dysfunctional families, weight loss and dieting, and stressful experiences and perceived pressure. The three most commonly cited factors contributing to recovery were supportive nonfamilial relationships, therapy, and maturation. DISCUSSION: Individuals with anorexia nervosa perceive both external (family environment) and personal factors (dieting and stress) as contributory to their disorders. The results underscore the importance of interpersonal factors in recovery from anorexia nervosa and suggest that attention to this area in treatment may be beneficial.

Adult↗
PubMed2003

Role of exposure with response prevention in cognitive-behavioral therapy for bulimia nervosa: three-year follow-up results.

BACKGROUND: Previous studies have not reported the longer-term outcome of exposure-based treatments for bulimia nervosa. The current study evaluated the 3-year outcome of a randomized clinical trial that compared the additive efficacy of exposure-based versus nonexposure-based behavioral treatments (BT) with a core of cognitive-behavior therapy (CBT). METHODS: One hundred thirteen women participated in the original treatment trial and attended a 3-year follow-up assessment. Eating disorder diagnoses and primary, secondary, and tertiary outcome measures were assessed. The impact of treatment completion on symptomatology and the stability of treatment effects over time were evaluated. RESULTS: At the 3-year follow-up, 85% of the sample had no current diagnosis of bulimia nervosa and 69% had no current eating disorder diagnoses of any sort. Failure to complete CBT was associated with inferior outcome. No clear advantages were evident for participants who completed BT in addition to CBT. For subjects who did complete both CBT and BT, outcome was mostly stable from posttreatment to follow-up. No differential effects were found for exposure versus nonexposure-based treatments at 3-year follow-up. DISCUSSION: The results of the current study compare favorably with other treatment outcome studies for bulimia nervosa and suggest that treatment gains are maintained after 3 years.

Adolescent↗
PubMed2003

Genetic and environmental contributions to obesity and binge eating.

OBJECTIVE: Binge eating is present in a substantial proportion of obese individuals. A tendency toward obesity has been identified as a risk factor for eating disorders such as bulimia nervosa and binge eating disorder. The purpose of this article was to determine the extent of overlap between genetic and environmental factors that contribute to the liability to obesity and binge eating. RESEARCH METHOD: In a population-based sample of 2163 female twins, we conducted bivariate twin modeling to explore the relation between the genetic and environmental risk factors for obesity and binge eating. RESULTS: Bivariate twin modeling revealed substantial heritability for obesity (0.86: 95% CI, 0.77-0.94), moderate heritability for binge eating (0.49: 95% CI, 0.38-0.61), and a modest genetic correlation of +.34 (95% CI, 0.19-0.50) between the two traits. CONCLUSIONS: Both binge eating and obesity are heritable conditions, and there seems to be only modest overlap in the genetic risk factors that increase liability to each condition.

Adolescent↗
PubMed2003

False discoveries and models for gene discovery.

In the search for genes underlying complex traits, there is a tendency to impose increasingly stringent criteria to avoid false discoveries. These stringent criteria make it hard to find true effects, and we argue that it might be better to optimize our procedures for eliminating and controlling false discoveries. Focusing on achieving an acceptable ratio of true- and false-positives, we show that false discoveries could be eliminated much more efficiently using a stepwise approach. To avoid a relatively high false discovery rate, corrections for 'multiple testing' might also be needed in candidate gene studies. If the appropriate methods are used, detecting the proportion of true effects appears to be a more important determinant of the genotyping burden than the desired false discovery rate. This raises the question of whether current models for gene discovery are shaped excessively by a fear of false discoveries.

Data Interpretation, Statistical↗
PubMed2003

Temperament, childhood environment and psychopathology as risk factors for avoidant and borderline personality disorders.

OBJECTIVE: To evaluate childhood experiences (neglect and abuse), temperament and childhood and adolescent psychopathology as risk factors for avoidant and borderline personality disorders in depressed outpatients. METHOD: One hundred and eighty depressed outpatients were evaluated for personality disorders. Risk factors of childhood abuse, parental care, temperament, conduct disorder symptoms, childhood and adolescent anxiety disorders, depressive episodes, hypomania and alcohol and drug dependence were obtained by questionnaires and interviews. RESULTS: Avoidant personality disorder can be conceptualized as arising from a combination of high harm avoidance (shy, anxious), childhood and adolescent anxiety disorders and parental neglect. Borderline personality disorder can be formulated as arising from a combination of childhood abuse and/or neglect, a borderline temperament (high novelty seeking and high harm avoidance), and childhood and adolescent depression, hypomania, conduct disorder and alcohol and drug dependence. CONCLUSIONS: Combinations of risk factors from the three domains of temperament, childhood experiences and childhood and adolescent psychopathology make major contributions to the development of avoidant and borderline personality disorders.

Adolescent↗
PubMed2003

A framework for controlling false discovery rates and minimizing the amount of genotyping in the search for disease mutations.

OBJECTIVES: To develop a method for designing studies to find disease mutations that can achieve a set of goals with respect to proportions of false and true discoveries with the minimum amount of genotyping. METHODS: Derivation of an analytical framework supplemented with simulation techniques. The approach is illustrated for a fine mapping study and a whole-genome linkage disequilibrium scan. RESULTS: The use of multiple stages where earlier stages are characterized by very high false discovery rates (FDR) followed by an abrupt change to the required FDR in the final stage results in a 50-75% reduction in genotyping. The proportion of true discoveries is a much more important determinant of the genotyping burden than the FDR. Neither sample size nor controlling the false discoveries will present major problems in whole-genome LD scans but the amount of genotyping will be extremely large even if the study is completely designed to minimize genotyping. CONCLUSIONS: The proposed statistical framework presents a simple and flexible approach to determine the design parameters (e.g. sample size, p values at which tests need to be performed at each stage) that minimize the genotyping burden given a set of goals for the percentage of true and false discoveries.

Chromosome Mapping↗
PubMed2003

The relation between eating disorders and components of perfectionism.

OBJECTIVE: The authors' goal was to explore the relation between perfectionism and psychopathology, including eating disorders. METHOD: Using logistic regression, the authors calculated odds ratios for the associations between perfectionism subscale scores and psychiatric disorders in 1,010 female twins who completed the Multidimensional Perfectionism Scale and participated in diagnostic interviews. RESULTS: Elevated concern over mistakes was associated with anorexia and bulimia nervosa but not with other psychiatric disorders. Doubts about actions was associated with eating and anxiety disorders. Multivariable models confirmed that higher scores on the subscales for concern over mistakes and doubts about actions were most strongly associated with eating disorders. CONCLUSIONS: The aspect of perfectionism captured by scores on a subscale measuring concern over mistakes may be particularly associated with eating disorders and not generically predictive of psychopathology.

Adult↗
PubMed2002

Medical and psychiatric morbidity in obese women with and without binge eating.

OBJECTIVE: To determine the prevalence of obesity and binge eating in a population-based sample of female twins and to examine whether the presence of binge eating was associated with a greater risk for medical and psychiatric disorders in obese women. METHOD: A population-based study of twins who were born between 1934 and 1971 and both members responded to a mailed questionnaire (individual response rate was conservatively estimated to be 64%). Data for the present study are from the first and third interview waves. In Wave 1 (1987-1989), we assessed 92% of the eligible individuals (N = 2,163), 90% face-to-face and the remainder by telephone. We assessed lifetime history of psychiatric disorders, major medical disorders, health limitations, health satisfaction, and an array of personality and attitudinal measures. RESULTS: Obese women with binge eating reported greater health dissatisfaction and higher rates of major medical disorders than obese women without binge eating. Binge eating was also associated with higher lifetime prevalence of major depression, panic disorder, phobias, and alcohol dependence. Obese women with binge eating scored higher on neuroticism and symptom scales measuring depression, anxiety/phobia, and neurovegetative symptoms (i.e., insomnia, agitation, retardation, and obsessive-compulsive traits). DISCUSSION: The presence of binge eating in obese women is a marker for greater medical and psychiatric morbidity.

Adult↗
PubMed2002

The subtypes of major depression in a twin registry.

OBJECTIVE: The subtypes of major depression (MD) remain incompletely understood. While there is consensus about the existence of MD with 'typical' vegetative features, further data are required to evaluate the existence of MD with atypical features. METHOD: Assessment of MD symptomatology in year prior to interview was available in 6846 individual twins from a population-based twin registry. The nine 'A' criteria for DSM-IV MD were unpacked so that the nature of sleep disturbance, appetite and weight changes, and motoric alterations were recorded. Latent class analysis was used to create an empirical typology of MD. RESULTS: Seven latent classes appeared to provide the best representation of the data. The most severe of these classes had interpretable profiles corresponding to typical MD, atypical MD, and 'minor' but seemingly important depressive states. These classes were generally more deviant than a comparison group for nearly all available validators. There tended to be a gradient with the typical class being most extreme, minor depressive classes the least extreme, and the atypical class having an intermediate position. CONCLUSIONS: Our findings support the existence of atypical depression as a phenomenological subtype of MD. Besides the differences in symptom patterns, there are many more similarities than differences across a range of external validators. Similar to other reports, we found evidence of the importance and morbidity of depressive symptomatology that does not meet the DSM-IV MD thresholds.

Adult↗