Biomedical subjects

Kenneth S Kendler

Publications and source records attributed to Kenneth S Kendler.

At least 55 records · Page 3Linked to original sources

PubMed2005

The differential impact of risk factors on illicit drug involvement in females.

BACKGROUND: Initiation of drug use and progression to abuse/dependence involve complex pathways. Potential risk factors may correlate with initiation or progression or both. Are there risk factors that associate with illicit drug use or illicit drug abuse/dependence? Is the magnitude of the association the same for use and abuse/dependence? Does this pattern of association differ across categories of drugs? METHODS: We used data from female-female adult twins to assess the association of 26 putative risk factors with use and abuse/dependence of six illicit psychoactive drugs. Drug involvement was represented by independent dichotomous outcomes and by a single ordinal variable. Odds ratios were obtained by logistic regression and a continuation ratio was used to test the magnitude of association. RESULTS: Factors associate in similar patterns with different drug categories. Some associated factors interact only with initiation while others relate with both stages. There is a stronger association of significant socio-demographic factors with drug use while the psychiatric diagnoses are more strongly associated with progression to abuse/dependence. CONCLUSIONS: Risk factors may be use-specific, abuse/dependence-specific or common to use and abuse/dependence. The trend of associations is similar across different illicit drugs. This suggests complex, interacting pathways that determine drug habits in individuals. These results are hypothesis-generating and future studies of causal relationships may draw from the outcomes presented in these analyses.

Adolescent↗

PubMed2005

Lifetime risk and persistence of psychiatric disorders across ethnic groups in the United States.

BACKGROUND: Recent research in the United States has demonstrated striking health disparities across ethnic groups. Despite a longstanding interest in ethnic disadvantage in psychiatric epidemiology, patterns of psychiatric morbidity across ethnic groups have never been examined in a nationally representative sample. METHOD: Ethnic differences in psychiatric morbidity are analyzed using data from the National Comorbidity Survey (NCS). The three largest ethnic groups in the United States--Hispanics, Non-Hispanic Blacks and Non-Hispanic Whites were compared with respect to lifetime risk and persistence of three categories of psychiatric disorder: mood disorder, anxiety disorder, and substance use disorder. RESULTS: Where differences across ethnic groups were found in lifetime risk, socially disadvantaged groups had lower risk. Relative to Non-Hispanic Whites, Hispanics had lower lifetime risk of substance use disorder and Non-Hispanic Blacks had lower lifetime risk of mood, anxiety and substance use disorders. Where differences were found in persistence of disorders, disadvantaged groups had higher risk. Hispanics with mood disorders were more likely to be persistently ill as were Non-Hispanic Blacks with respect to both mood disorders and anxiety disorders. Closer examination found these differences to be generally consistent across population subgroups. CONCLUSIONS: Members of disadvantaged ethnic groups in the United States do not have an increased risk for psychiatric disorders. Members of these groups, however, do tend to have more persistent disorders. Future research should focus on explanations for these findings, including the possibility that these comparisons are biased, and on potential means of reducing the disparity in persistence of disorders across ethnic groups.

Adolescent↗

PubMed2005

DSM criteria for major depression: evaluating symptom patterns using latent-trait item response models.

BACKGROUND: Expert committees of clinicians have chosen diagnostic criteria for psychiatric disorders with little guidance from measurement theory or modern psychometric methods. The DSM-III-R criteria for major depression (MD) are examined to determine the degree to which latent trait item response models can extract additional useful information. METHOD: The dimensionality and measurement properties of the 9 DSM-III-R criteria plus duration are evaluated using dichotomous factor analysis and the Rasch and 2 parameter logistic item response models. Quantitative liability scales are compared with a binary DSM-III-R diagnostic algorithm variable to determine the ramifications of using each approach. RESULTS: Factor and item response model results indicated the 10 MD criteria defined a reasonably coherent unidimensional scale of liability. However, person risk measurement was not optimal. Criteria thresholds were unevenly spaced leaving scale regions poorly measured. Criteria varied in discriminating levels of risk. Compared to a binary MD diagnosis, item response model (IRM) liability scales performed far better in (i) elucidating the relationship between MD symptoms and liability, (ii) predicting the personality trait of neuroticism and future depressive episodes and (iii) more precisely estimating heritability parameters. CONCLUSIONS: Criteria for MD largely defined a single dimension of disease liability although the quality of person risk measurement was less clear. The quantitative item response scales were statistically superior in predicting relevant outcomes and estimating twin model parameters. Item response models that treat symptoms as ordered indicators of risk rather than as counts towards a diagnostic threshold more fully exploit the information available in symptom endorsement data patterns.

Adolescent↗

PubMed2005

Genetic and environmental influences on illicit drug use and tobacco use across birth cohorts.

BACKGROUND: The prevalence of use of many psychoactive substances has changed considerably in recent years. While genetic factors impact on overall risk for substance use, we know little about whether the etiological importance of these factors differs across birth cohorts. One theory, which postulates that heritability of deviant traits increases in permissive environments, predicts a positive relationship across cohorts between prevalence and heritability of substance use. METHOD: The lifetime history of use of tobacco, cannabis, cocaine, sedatives and stimulants were assessed in 4826 twins from male-male and female-female pairs born in Virginia from 1934 to 1974. Using empirical methods based on prevalence by birth year, these twins were divided into three cohorts for each substance (e.g. for cannabis 1934-1953, 1954-1968 and 1969-1974). Structural equation modeling was performed using the Mx software package. RESULTS: Prevalence rates for psychoactive substance use differed substantially across cohorts, most markedly for cocaine, sedatives and stimulants, which were highest in the 1958-1963 cohort. However, for all substances, the best-fit model constrained estimates of the etiological role of genetic and environmental risk factors to be equal across both sex and cohort. CONCLUSIONS: We found no evidence in this sample for any systematic relationship between heritability and prevalence of psychoactive substance use--which should be a rough index of drug availability and/or acceptability. This sample had reasonable power to detect large changes in heritability across cohorts and at least moderate power to detect relatively small changes.

Adult↗

PubMed2005

Age at onset and familial risk for major depression in a Swedish national twin sample.

BACKGROUND: In many biomedical disorders, early age at onset (AAO) is an index of high liability to illness which is manifest by an increased risk of illness in relatives. Most but not all prior studies report such a pattern for major depression (MD). METHOD: Lifetime MD and AAO were assessed at personal interview using modified DSM-III-R criteria in 13864 twin pairs, including 4229 onsets of MD, from the Swedish National Twin Registry. Analyses were conducted using Cox proportional hazards models. RESULTS: Controlling for year of birth, gender, zygosity, co-twin history of MD and the interaction of zygosity and co-twin history, the best-fit model showed a significant main effect and a quadratic effect of AAO of MD in the co-twin on the log hazard ratio for MD in the index twin. When examined together, these effects predicted that from the ages of 15 to approximately 35 years, AAO of MD is moderately negatively related to risk of illness in relatives. However, past age 35, the function flattens out, with little change of risk in relatives with further increases of AAO. Even when the co-twin had a late AAO, the risk in the index twin substantially exceeded that seen when the co-twin had no history of MD. CONCLUSION: In this large sample, AAO is a meaningful, albeit modest, index of familial liability to MD. The relationship is nonlinear and results largely from an increased liability in individuals with an early AAO. These results should be interpreted in the context of the limitations of long-term recall.

Age of Onset↗

PubMed2005

The types of regular cigarette smokers: a latent class analysis.

The present study sought to refine cigarette smoking exposure by examining whether individuals with a history of regular cigarette smoking could be classified into meaningful subgroups based on their smoking habits, nicotine dependence, and quit attempts. Data were obtained from 3,025 male and female twins aged 22-59 years who participated in two longitudinal studies based on the Virginia Twin Registry. Latent class analysis was used to identify the number and nature of subgroups of smokers reporting similar smoking habits based on 18 characteristics. Estimates of prevalence for different classes of smoking were obtained along with expected frequencies of endorsements for each smoking behavior by class. Distributions of demographic characteristics, psychopathology, and personality were examined as external validators. The results demonstrated considerable heterogeneity and revealed eight classes of smokers who differed in their degree of nicotine dependence, cessation attempts, and ability to quit smoking. Smoking classes ranged from individuals who were all former smokers with low nicotine dependence who attempted to quit once and were successful, to individuals who were all current smokers with little desire to quit, to individuals with high nicotine dependence with multiple quit attempts, only a subset of which were successful. Estimates of prevalence for each class were 9%-20%. Our findings support the idea that regular cigarette smokers are highly heterogeneous and highlight the need for smoking exposure refinement in future studies. Acknowledging the complexity of cigarette smoking and classifying smokers into more specific subgroups based on their smoking behavior in future studies will enable more accurate evaluation of disease etiology and risk and could lead to more appropriate smoking cessation interventions.

Adult↗

PubMed2005

Abnormal infant neurodevelopment predicts schizophrenia spectrum disorders.

OBJECTIVE: The aim of this study was to detect infants who carry a schizophrenic genotype and study the development of schizophrenia spectrum disorders (SZSD) from birth. INTRODUCTION: In the 1940s, Bender described uneven maturation in childhood schizophrenics and in 1952 found this in the infant histories of 6 schizophrenic children. METHODS: We tested a possible index for defective neural integration in infants termed "pandysmaturation" (PDM). This required retarded cranial growth plus retarded and erratic gross motor development on a single exam. Twelve offspring of hospitalized schizophrenic mothers and 12 infants in a "Well Baby Clinic," were examined 10 times between birth and 2 years of age. Psychiatric interviews and psychological testing were done at 10, 15, and 22 years of age, plus follow-up at 27-35 years of age. RESULTS: Six infants had PDM at 2, 6, or 13 months of age. Five individuals have been blindly diagnosed (by KSK) as having lifetime SZSD; all 5 had PDM before 8 months. Chi-square one-tailed tests confirmed the predictions: (1) PDM was related to subsequent SZSD (chi(2) = 11.43; p < 0.0005); (2) schizophrenic mothers had more infants with PDM than nonschizophrenic mothers (chi(2) = 3.28; p < 0.05); and (3) schizophrenic mothers had more SZSD offspring than nonschizophrenic mothers (chi(2) = 6.39; p < 0.0125). DISCUSSION: These first behavioral observations of aberrant neurodevelopment in pre- SZSD infants support the evidence of early neurodevelopmental disorder seen in studies of brain pathology in SZSD adults.

Adolescent↗

PubMed2005

The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history.

BACKGROUND: This article is the first report of the Irish Affected Sib Pair Study of Alcohol Dependence, whose goal is to detect the genomic location of susceptibility loci for alcohol dependence (AD). This article describes phenotypic characteristics of the probands, siblings, and parents included in the sample and examines agreement among different sources of diagnostic information, including the validity of family history (FH) assessment. METHODS: Structured diagnostic interviews were conducted with 1414 individuals from 591 families ascertained in Ireland. AD was assessed among 1201 probands and affected siblings with use of the Semi-Structured Assessment for the Genetics of Alcoholism and among 213 parents with use of a modified version of the Structured Clinical Interview for DSM. Probands and siblings were also assessed for drinking history, comorbid disorders, and other clinical characteristics. FH reports based on FH-Research Diagnostic Criteria were obtained for 1113 of these individuals as well as for 3652 first-degree relatives who were not interviewed. RESULTS: Sample characteristics confirm the severity of AD among the affected individuals. Agreement between FH ratings and diagnoses based on direct interviews was high for both parent-offspring and sibling-sibling comparisons (e.g., positive and negative predictive values > 80% for a range of cutoffs). Agreement among individuals about their family members was also high for a single item (1 month or more of drinking problems, tetrachoric r = 0.86-0.98), the total number of DSM-IV AD symptoms (polychoric r = 0.86-0.96), and classifications based on a range of cutoffs (kappa = 0.75-0.80). Use of multiple informants improved classification accuracy only slightly (6-10%). CONCLUSIONS: The authors successfully collected data for a large sample of affected sibling pairs for molecular genetic analysis of AD. Individuals with AD were able to provide accurate evaluations of alcoholism symptoms in their parents and adult siblings. A single screening item performed nearly as well as the full scale. Collecting information from multiple informants may not be cost effective for the gain in predictive accuracy. FH information collected from affected informants can be a valuable source of diagnostic information for family studies of alcoholism.

Adult↗

PubMed2005

Psychiatric genetics: a methodologic critique.

Psychiatric genetics, which is growing in size and influence within psychiatry, employs four major research paradigms: 1) basic genetic epidemiology, 2) advanced genetic epidemiology, 3) gene finding methods, and 4) molecular genetics. Paradigms 1 and 2 study aggregate genetic risk factors inferred from patterns of resemblance in relatives. Paradigms 3 and 4 study individual susceptibility genes localized on the human genome. Paradigms 1, 2, and 3 are statistical in nature, while paradigm 4 is biological. Genetic risk factors reflect the statistical signals from susceptibility genes. Whether it will be possible to identify all the susceptibility genes that underlie genetic risk factors is uncertain. Furthermore, given current research methods, the inability to detect susceptibility genes cannot disconfirm evidence for genetic risk factors. While paradigms 3 and 4 can provide great explanatory power by tracing etiologic pathways back to basic biological mechanisms, genetic epidemiology can also provide important etiologic insights, albeit of a less basic nature. While paradigms 3 and 4 may eventually replace paradigms 1 and 2, this shift is unlikely to occur quickly. Therefore, the field of psychiatric genetics would do best to integrate these four paradigms, stressing their relative strengths and limitations. This integration can be best done within an overall framework of explanatory pluralism that values a range of reductive explanations across varying levels of biological and psychological complexity.

Biological Psychiatry↗

PubMed2005

Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether a haplotype in the dystrobrevin binding protein 1 (DTNBP1) gene previously associated with schizophrenia not only increases the susceptibility to psychotic illness but also to a more or less clinically specific form of psychotic illness. METHOD: In the Irish Study of High-Density Schizophrenia Families, subjects with psychotic illness (N=755) were given lifetime ratings of clinical features according to the Operational Criteria Checklist for Psychotic Illness. Exploratory and confirmatory factor analyses were used to extract five factors-hallucinations, delusions, negative, manic, and depressive symptoms-and to create factor-derived scores. The family-based transmission disequilibrium test operationalized in the program TRANSMIT was used to determine whether a high-risk haplotype in the DTNBP1 gene was overtransmitted to subjects in the upper 20th and 40th percentiles for each factor score. These results were compared to baseline overtransmission by examining the empirical distribution of chi-square statistics in groups of 5,000 replicates in which 20% and 40% of ill subjects were randomly selected. This analysis was done for both narrow and broad definitions of psychotic illness. RESULTS: Subjects in the upper 40th percentile for the negative symptom factor--in both the narrowly (p=0.004) and broadly (p=0.01) defined illness groups--were more likely to inherit the high-risk haplotype than would be expected by chance. No other significant relationships between clinical features and high-risk haplotype transmission were observed. CONCLUSIONS: The etiologically relevant variation in DTNBP1, which is in presumptive linkage disequilibrium with the high-risk haplotype, may predispose individuals to a form of psychotic illness associated with high levels of negative symptoms. This finding supports previous evidence suggesting that genetic factors influence the clinical heterogeneity of schizophrenia.

Carrier Proteins↗

PubMed2005

Sex differences in the relationship between social support and risk for major depression: a longitudinal study of opposite-sex twin pairs.

OBJECTIVE: Compared to men, women have larger and more intimate social networks and higher rates of major depression. Prior studies have suggested that women are more sensitive to the depressogenic effects of low social support, but most of these studies had substantial methodologic limitations. METHOD: In two interview waves at least 1 year apart, 1,057 pairs of opposite-sex dizygotic twin pairs ascertained from a population-based register were assessed. The authors predicted risk of major depression in the year before the wave 2 interview from levels of social support assessed at wave 1. RESULTS: Women reported higher levels of global social support than their twin brothers. Global social support at wave 1 predicted risk for major depression at wave 2 significantly more strongly in female than in male members of these pairs, and the same effect was seen when the analysis controlled for the history of major depression in the year prior to wave 1. Women were more sensitive than men to the depressogenic effects of low levels of social support, particularly from the co-twin, other relatives, parents, and spouses. Levels of social support did not explain the sex difference in risk for major depression. CONCLUSIONS: Emotionally supportive social relationships are substantially more protective against major depression for women than for men. While these effects cannot explain sex effects on the prevalence of major depression, they do suggest important sex differences in pathways of risk. Clarification of the nature of the causal links between low social support and depression in women is needed.

Adult↗

PubMed2005

Toward a philosophical structure for psychiatry.

This article, which seeks to sketch a coherent conceptual and philosophical framework for psychiatry, confronts two major questions: how do mind and brain interrelate, and how can we integrate the multiple explanatory perspectives of psychiatric illness? Eight propositions are proposed and defended: 1) psychiatry is irrevocably grounded in mental, first-person experiences; 2) Cartesian substance dualism is false; 3) epiphenomenalism is false; 4) both brain-->mind and mind-->brain causality are real; 5) psychiatric disorders are etiologically complex, and no more "spirochete-like" discoveries will be made that explain their origins in simple terms; 6) explanatory pluralism is preferable to monistic explanatory approaches, especially biological reductionism; 7) psychiatry must move beyond a prescientific "battle of paradigms" to embrace complexity and support empirically rigorous and pluralistic explanatory models; 8) psychiatry should strive for "patchy reductionism" with the goal of "piecemeal integration" in trying to explain complex etiological pathways to illness bit by bit.

Biological Psychiatry↗

PubMed2005

"A gene for...": the nature of gene action in psychiatric disorders.

A central phrase in the new "GeneTalk" is "X is a gene for Y," in which X is a particular gene on the human genome and Y is a complex human disorder or trait. This article begins by sketching the historical origins of this phrase and the concept of the gene-phenotype relationship that underlies it. Five criteria are then proposed to evaluate the appropriateness of the "X is a gene for Y" concept: 1) strength of association, 2) specificity of relationship, 3) noncontingency of effect, 4) causal proximity of X to Y, and 5) the degree to which X is the appropriate level of explanation for Y. Evidence from psychiatric genetics is then reviewed that address each of these criteria. The concept of "a gene for..." is best understood as deriving from preformationist developmental theory in which genes-like preformationist anlagen-"code for" traits in a simple, direct, and powerful way. However, the genetic contribution to psychiatric disorders fails to meet any of the five criteria for the concept of "X is a gene for Y." The impact of individual genes on risk for psychiatric illness is small, often nonspecific, and embedded in complex causal pathways. The phrase "a gene for..." and the preformationist concept of gene action that underlies it are inappropriate for psychiatric disorders.

Gene Expression Regulation↗

PubMed2005

Personality and comorbidity of common psychiatric disorders.

BACKGROUND: We know little about the degree to which comorbidity, socommonly seen among psychiatric disorders, arises from variation in normal personality. AIMS: To study the degree to which variation in normal personality accounts for the comorbidity of eight common psychiatric and substance use disorders. METHOD: Internalising disorders (major depression, generalised anxiety and panic disorders, phobias), externalising disorders (alcohol and drug dependence, antisocial personality and conduct disorders) and personality dimensions of neuroticism, extraversion and novelty seeking were assessed in 7588 participants from a population-based twin registry. The proportion of comorbidity explained by each personality dimension was calculated using structural equation modelling. RESULTS: Neuroticism accounted for the highest proportion of comorbidity within internalising disorders (20-45%) and between internalising and externalising disorders (19-88%). Variation in neuroticism and novelty seeking each accounted for a modest proportion (10-12% and 7-14%, respectively) of the comorbidity within externalising disorders. Extraversion contributed negligibly. CONCLUSIONS: High neuroticism appears to be a broad vulnerability factor for comorbid psychiatric disorders. Novelty seeking is modestly important for comorbid externalising disorders.

Adult↗

PubMed2005

The differential heritability of regular tobacco use based on method of administration.

Several large studies have demonstrated that the liability to smoke cigarettes is strongly genetically influenced. However, the role of genetic and environmental risk factors in the use of other common forms of tobacco use has yet to be studied. Data on the regular use of cigarettes, cigars, pipes, dip (moist snuff), and chewing tobacco from 2634 male twins were analyzed with ACE structural equation models. Twin similarity for regular cigarette and dip use was largely genetic in origin. However, twin resemblance for chewing tobacco was just about equally the result of genes and shared environment, and twin similarity for use of pipes and cigars was entirely the result of shared environmental factors. Thus, the genetic influences on the liability for regular tobacco use appear to vary based on tobacco type. The causes for the use of different forms of tobacco are complex and worthy of further study.

Adult↗

PubMed2005

Epistatic and environmental control of genome-wide gene expression.

All etiological studies of complex human traits focus on analyzing the causes of variation. Given this complexity, there is a premium on studying those processes that mediate between gene products and cellular or organismal phenotypes. Studies of levels of gene expression could offer insight into these processes and are likely to be especially useful to the extent that the major sources of their variation are known in normal tissues. The classical study of monozygotic (MZ) and dizygotic (DZ) twins was employed to partition the genetic and environmental influences in gene expression for over 6500 human genes measured using microarrays from lymphoblastoid cell lines. Our results indicate that mean expression levels are correlated about .3 in monozygotic (MZ) and .0 in dizygotic (DZ) twins suggesting an overall epistatic regulation of gene expression. Furthermore, the functions of several of the genes whose expression was most affected by environmental effects, after correction for measurement error, were consistent with their known role in mediating sensitivity to environmental influences.

Adolescent↗

PubMed2004

Association study of the Epac gene and tobacco smoking and nicotine dependence.

Exchange protein directly activated by cAMP (Epac) has been shown to increase its expression in rat prefrontal cortex after self-administration of nicotine. [Konu et al. 2001: Brain Res 909:194-203]. We investigated the role of the human ortholog of Epac in tobacco smoking and nicotine dependence (ND). Using a case-control design, we typed 5 SNPs in this gene in 688 subjects, of whom 244 were non-smokers, 215 were Low-ND smokers, and 229 were High-ND smokers. We tested allele and genotype association to smoking initiation (SI) and progression to ND. Three of the five typed SNPs showed modest allele association with progression to ND. Weak association with SI was also observed for one SNP. Considering the function of the gene in cellular signal transduction pathway, its elevated expression after nicotine self-administration, and multiple markers association with both SI and progression to ND, it is plausible to suggest that variants in Epac contribute to the liability to ND.

Alleles↗

PubMed2004

Forms of cannabis and cocaine: a twin study.

Cannabis and cocaine are illicit psychoactive substances that have fallen under intense scrutiny by epidemiologists and behavioral geneticists. However, most analyses have used a composite variable to represent the use of these two drugs. For example, the composite variable of cannabis use often includes use of marijuana or hashish. Similarly, cocaine use involves different preparations (crack vs. cocaine hydrochloride) and varying routes of administration (intranasal insufflation vs. smoking). While there is some epidemiological evidence for the difference in addictive potentials between crack and intranasal cocaine, genetically informative studies have not examined the relationship between the forms of cannabis or cocaine. We used data from male and female same-sex twin pairs to examine the extent of genetic, shared environmental, and unique environmental overlap between (i) marijuana and hashish for cannabis use and (ii) intranasal and crack cocaine for cocaine use. Bivariate Cholesky models were fit using the structural equation modeling software Mx. Our results indicate that for both drugs, the individual drug forms show a complete overlap of genetic factors and a substantial overlap of shared environmental influences. While marijuana and hashish share a moderate proportion of their unique environment, crack and intranasal cocaine only show a modest overlap of unique environmental factors, adding some evidence for form-specific environmental factors. In conclusion, there is substantial overlap of familial factors between forms of a single drug and preference is primarily determined by unique environmental influences. These findings also reinforce the validity of composite variables in epidemiological and genetic research.

Adult↗