Biomedical subjects

Kenneth S Kendler

Publications and source records attributed to Kenneth S Kendler.

At least 37 records · Page 2Linked to original sources

PubMed2006

Association of the phosphatase and tensin homolog gene (PTEN) with smoking initiation and nicotine dependence.

Since PTEN (phosphatase and tensin homolog) has elevated expression in rat brain (amygdala) after chronic administration of nicotine and the PTEN gene is located in the vicinity of the chromosome 10q23 linkage peak in a genome-scan study of nicotine dependence, PTEN seems a plausible candidate gene for smoking behavior. To test this hypothesis, we use a three-group case-control design and genotype five SNPs in the PTEN gene. We compare allele and genotype frequencies between the smokers and nonsmokers and between the low nicotine dependent and high nicotine dependent subjects. Three SNPs in the PTEN gene are significantly associated with smoking initiation (rs1234221, P = 0.0311; rs1234213, P = 0.0002; and rs2735343, P = 0.0028). Rs1234213 also shows association with nicotine dependence (P = 0.0278). Haplotype analyses indicate that a major haplotype, 1-1-2-2-1 for rs1234221-rs2299939-rs1234213-rs2735343-rs70184, is associated with smoking initiation. A minor haplotype (about 3%), 1-2-2-2-1 for the same five SNPs, is observed only in the high nicotine dependence group. These results suggest that the PTEN gene may be involved in the etiology of both smoking initiation and nicotine dependence.

Alleles↗

PubMed2006

Personality and major depression: a Swedish longitudinal, population-based twin study.

CONTEXT: Prior studies suggest that the personality traits of neuroticism and extroversion may be related to the liability to major depression (MD). OBJECTIVE: To clarify the magnitude and nature of the association between neuroticism and extroversion and the risk for MD. DESIGN: Longitudinal population-based twin cohort. SETTING: General community. PARTICIPANTS: A total of 20 692 members of same-sex twin pairs from the population-based Swedish Twin Registry who completed a self-report questionnaire assessing neuroticism and extroversion in 1972 and 1973 and were personally interviewed for lifetime history of MD more than 25 years later.Main Outcome Measure Lifetime history of modified DSM-IV MD. RESULTS: Levels of neuroticism strongly predicted the risks for both lifetime and new-onset MD. Twin modeling indicated that the association between neuroticism and MD resulted largely from shared genetic risk factors, with a genetic correlation of +0.46 to +0.47. Levels of extroversion were weakly and inversely related to the risks for lifetime and new-onset MD. This effect disappeared when we controlled for the level of neuroticism. Twin modeling produced similar results. CONCLUSIONS: Results from both longitudinal and genetic analyses support the hypothesis that neuroticism strongly reflects the liability to MD. This association arises largely because neuroticism indexes the genetic risk for depressive illness. However, substantial proportions of the genetic vulnerability to MD are not reflected in neuroticism. By contrast, extroversion is only weakly related to risk for MD.

Adult↗

PubMed2006

Associations among postpartum depression, eating disorders, and perfectionism in a population-based sample of adult women.

OBJECTIVE: The current study investigated associations among eating disorders, depressive symptoms during pregnancy and postpartum, and perfectionism in a population-based sample of women. METHOD: Females who reported > or = 1 pregnancy (N = 1,119) completed questionnaires assessing perfectionism, eating disorder symptomatology, and depression during pregnancy and postpartum. Information regarding participants' history of major depressive disorder (MDD) was also available from structured psychiatric interviews completed during a previous wave of data collection. RESULTS: Depressive symptoms during pregnancy and postpartum were high among women with a history of eating disorders. Both binge eating disorder (BED) and bulimia nervosa (BN) were positively associated with symptoms of postpartum depression (PPD), even when lifetime MDD was controlled. However, logistic regression indicated that women with a history of BN and BED are at particular risk of developing PPD symptomatology. Linear regression analyses conducted with the subset of the sample who endorsed a PPD screening item suggested that the severity of PPD symptomatology may be attributable to Concern Over Mistakes, a specific aspect of perfectionism. CONCLUSION: These results highlight the importance of assessing specific features of perfectionism. In addition, they suggest that women with BN, BED, or high Concern over Mistakes may be at particular risk of developing PPD symptoms, and could benefit from prenatal screening.

Adult↗

PubMed2006

Molecular genetic studies of schizophrenia.

The study of schizophrenia genetics has confirmed the importance of genes in etiology, but has not so far identified the relationship between observed genetic risks and specific DNA variants, protein alterations or biological processes. In spite of many limitations, numerous regions of the human genome give consistent, although by no means unanimous, support for linkage, which is unlikely to occur by chance. Two recent shifts have been evident in the field. First, a series of studies combining linkage and association analyses in the same family sets have identified promising candidate genes (DTNBP1, NRG1, G72/G30, TRAR4). Although a consensus definition of replication for genetic association in a complex trait remains difficult to achieve, the evidence for two of these (dystrobrevin binding protein 1 (DTNBP1), NRG1) is strong. Second, a series of studies combining association with functional investigation of changes in the associated gene in schizophrenia have also identified several candidate genes (COMT, RGS4, PPP3CC, ZDHHC8, AKT1). Somewhat surprisingly, the loci implicated by these studies have proven less robust in replication, although the number of replication studies remains small in several cases. Assessment of the combined evidence for the DTNBP1 gene gives some insight into the nature of the problems remaining to be solved.

Genetic Linkage↗

PubMed2006

A pediatric twin study of brain morphometry.

BACKGROUND: Longitudinal pediatric neuroimaging studies have demonstrated increasing volumes of white matter and regionally-specific inverted U shaped developmental trajectories of gray matter volumes during childhood and adolescence. Studies of monozygotic and dyzygotic twins during this developmental period allow exploration of genetic and non-genetic influences on these developmental trajectories. METHOD: Magnetic resonance imaging brain scans were acquired on a pediatric sample of 90 monozygotic twin pairs, 38 same-sex dyzygotic twin pairs, and 158 unrelated typically developing singletons. Structural equation modeling was used to estimate the additive genetic, common environment, and unique environment effects, as well as age by heritability interactions, on measures of brain volumes from these images. RESULTS: Consistent with previous adult studies, additive genetic effects accounted for a substantial portion of variability in nearly all brain regions with the notable exception of the cerebellum. Significant age by heritability interactions were observed with gray matter volumes showing a reduction in heritability with increasing age, while white matter volume heritability increased with greater age. CONCLUSION: Understanding the relative contributions of genetic and nongenetic factors on developmental brain trajectories may have implications for better understanding brain-based disorders and typical cognitive development.

Adolescent↗

PubMed2006

Identification of susceptibility loci for alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence.

BACKGROUND: Alcoholism is a phenotypically and probably genetically heterogeneous condition. Thus, one strategy for finding genes influencing liability to alcoholism is to study the components of alcoholism, which may be more directly related to the underlying pathophysiology than is clinical diagnosis. The goal of this study was to identify genomic regions containing susceptibility loci for alcohol-related traits. METHODS: A 4-cM dense whole-genome linkage study was conducted in the Irish Affected Sib Pair Study of Alcohol Dependence. Probands, affected siblings, and parents were evaluated by structured interview. Variance component linkage analysis was applied to data from 485 families for 5 measures: initial sensitivity and tolerance (based on scales from the self-report of the effects of ethanol; maximum drinks within 24 hours, an empirically derived factor score based on withdrawal symptoms, and age at onset of alcohol dependence. RESULTS: Evidence for linkage (p<0.005) was found on 9 chromosomes. For age at onset, 2 regions were found on chromosome 9 (highest Lod=2.3, p=0.0005). For initial level of response to alcohol, suggestive regions were on chromosomes 1 and 11 (highest Lod=2.9, p=0.0001 on chromosome 11), while those for tolerance signals were on chromosomes 1, 6, and 22. Maximum drinking was associated with regions on chromosomes 12 and 18. For withdrawal symptoms, the highest peak was on chromosome 2 (Lod=2.2, p=0.0007). CONCLUSIONS: Using quantitative measures of components of alcohol dependence, we identified several regions of the genome that may contain susceptibility loci for specific alcohol-related traits and merit additional study.

Adult↗

PubMed2006

A joint genomewide linkage analysis of symptoms of alcohol dependence and conduct disorder.

BACKGROUND: A large linkage peak for alcohol dependence (AD) was detected on chromosome 4q in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Are the susceptibility genes underlying this peak specific for AD or do they increase risk for externalizing disorders more generally? Can we, in the IASPSAD, replicate prior evidence for linkage to conduct disorder (CD)? METHODS: The 733 all possible sibling pairs in IASPSAD were typed for 1,020 short-tandem-repeat genetic markers. Univariate and bivariate linkage analyses were conducted by the program sequential oligogenic linkage analysis routines (SOLAR), for both the raw and the transformed number of symptoms of AD (ADsx) and number of symptoms of CD (CDsx). In the bivariate analyses, specificity was assessed by the ratio of the variance accounted for in ADsx and CDsx by the quantitative trait locus. RESULTS: In the univariate linkage analyses, no evidence for linkage to CDsx was found under the 4q peak for ADsx and the largest peaks for CDsx were seen on chromosomes 1q (LOD=3.16) and 14p (LOD=2.36). In the bivariate linkage analysis, the 4q peak had high specificity for AD (AD/CD ratio of 39.9). Several smaller peaks, on chromosomes 1, 7, and 10, had moderate specificity for CD but also impacted on risk for AD, with AD/CD ratios of 0.18 to 0.32. CONCLUSIONS: Genes under the 4q linkage peak for AD in the IASPSAD impact specifically on risk for AD rather than more broadly on risk for externalizing syndromes. Suggestive linkages were found in several locations for CD, 2 of which broadly replicate prior findings. The bivariate analyses identified genomic locations containing susceptibility loci that impacted on risk for both CDsx and ADsx.

Alcohol-Related Disorders↗

PubMed2006

The nature of genetic influences on behavior: lessons from "simpler" organisms.

Substantial advances have been made in recent years in the understanding of the genetic basis of behavior in "simpler" organisms, especially the mouse and the fruit fly Drosophila. The authors examine the degree of similarity between the genetic underpinnings of psychiatric illness and genetic influences on behavior in such simpler organisms. Six topics are reviewed: 1) the extent of natural genetic variation, 2) the multigenic nature of natural variation, 3) the impact of individual genes on multiple traits, 4) gene-environment interactions, 5) genetic effects on the environment, and 6) gene-by-sex interactions. The results suggest that the pattern of results emerging in psychiatric genetics is generally consistent with the findings of behavioral genetics in simpler organisms. Across the animal kingdom, individual differences in behavior are nearly always influenced by genetic factors which, in turn, result from a substantial number of individual genes, each with a small effect. Nearly all genes that affect behavior influence multiple phenotypes. The impact of individual genes can be substantially modified by other genes and/or by environmental experiences. Many animals alter their environment, and the nature of that alteration is influenced by genes. For some behaviors, the pathway from genes to behavior differs meaningfully in males and females. With respect to the broad patterns of genetic influences on behavior, Homo sapiens appears to be typical of other animal species.

Animals↗

PubMed2006

A population-based twin study of the relationship between neuroticism and internalizing disorders.

OBJECTIVE: The anxiety and depressive disorders exhibit high levels of lifetime comorbidity with one another. The authors examined how genetic and environmental factors shared by the personality trait neuroticism and seven internalizing disorders may help explain this comorbidity. METHOD: Lifetime major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, situational phobia, and neuroticism were assessed in over 9,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Multivariate structural equation models were used to decompose the correlations between these phenotypes into genetic and environmental components, allowing for sex-specific factors. RESULTS: Genetic factors shared with neuroticism accounted for between one-third and one-half of the genetic risk across the internalizing disorders. When nonsignificant gender differences were removed from the models, the genetic correlations between neuroticism and each disorder were high, while individual-specific environmental correlations were substantially lower. In addition, the authors could identify a neuroticism-independent genetic factor that significantly increased risk for major depression, generalized anxiety disorder, and panic disorder. CONCLUSIONS: There is substantial, but not complete, overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability across the internalizing disorders, helping to explain the high rates of comorbidity among the latter. This may have important implications for identifying the susceptibility genes for these conditions.

Adult↗

PubMed2006

Reflections on the relationship between psychiatric genetics and psychiatric nosology.

Research advances in psychiatric genetics have raised expectations that genetic findings might lead to major breakthroughs in psychiatric nosology. The author reviews the plausibility of these claims. Four areas are addressed. First, it is argued that familial aggregation of a single putative psychiatric syndrome provides at best limited evidence for the validity of that syndrome. Second, both traditional and molecular genetic strategies can supply important insights into major diagnostic conundrums. However, evidence that one or a few individual genes impact on risk for two disorders is not likely to resolve definitively the nosologic relationship between the two syndromes. Third, while gene-based essentialist models for psychiatric disorders are conceptually appealing, they are not well supported empirically. Gene discovery in psychiatry is, on its own, unlikely to allow us to "carve nature at its joints," thereby validating categorical psychiatric diagnoses. Fourth, the project to ground "messy" psychiatric categories on the firm foundation of genes-as an archetypal natural kind-may be fundamentally flawed because the very concept of "the gene" as a discrete entity is itself increasingly in doubt. Whereas psychiatric genetics has and will continue to provide important insights into the etiology of psychiatric and substance use disorders, it is not likely alone to provide deep answers to the complex and multifaceted problems facing psychiatric nosology.

Biological Psychiatry↗

PubMed2006

A Swedish national twin study of lifetime major depression.

OBJECTIVE: Substantial evidence supports the heritability of lifetime major depression. Less clear is whether genetic influences in major depression are more important in women than in men and whether genetic risk factors are the same in the two sexes. It is not known whether genetic effects on major depression are constant across historical cohorts. METHOD: Lifetime major depression was assessed at personal interview by modified DSM-IV criteria in 42,161 twins, including 15,493 complete pairs, from the national Swedish Twin Registry. Twin models were evaluated by using the program Mx. RESULTS: Model fitting indicated that the heritability of liability to major depression was significantly higher in women (42%) than men (29%) and the genetic risk factors for major depression were moderately correlated in men and women. No significant differences were seen in the etiologic roles of genetic and environmental factors in major depression in three cohorts spanning birth years 1900-1958. CONCLUSIONS: In the largest sample to date, lifetime major depression was moderately heritable, with estimates similar to those in prior studies. In accord with some but not other previous investigations, this study suggests both that the heritability of major depression is higher in women than in men and that some genetic risk factors for major depression are sex-specific in their effect. No evidence was found for differences in the roles of genetic and environmental risk factors in major depression in birth cohorts spanning nearly six decades.

Cohort Studies↗

PubMed2006

Toward a comprehensive developmental model for major depression in men.

OBJECTIVE: The multiple risk factors for major depression are interrelated through poorly understood developmental pathways. In 2002, the authors presented a developmental model for major depression in women. Based on similar methods, they here present an analogous model for men. METHOD: Using data from 2,935 adult male twins, interviewed twice over a 2-4-year period, the authors constructed, by means of structural equation modeling, an integrated etiologic model for major depression that predicts depressive episodes over 1 year from 18 risk factors conceptualized as five developmental "tiers" reflecting childhood, early adolescence, late adolescence, adulthood, and the last year. RESULTS: The best-fitting model, including six correlations and 76 paths, provided a good fit to the data, explaining 49% of the variance in the liability to depressive episodes. The overall results, similar to those seen in women, suggest that the development of major depression results from the action and interaction of three broad pathways of internalizing symptoms, externalizing symptoms, and adversity. Childhood parental loss and low self-esteem were more potent variables in the model in men than in women. Genetic risks for major depression had a broader spectrum of action in men than in women. The pathway to major depression through externalizing symptoms was not more prominent in men than in women. CONCLUSIONS: Major depression in men, as in women, is an etiologically complex disorder influenced by risk factors from multiple domains that act in developmental time. The similarities in etiologic pathways to major depression for men and women outweigh the modest differences.

Adolescent↗

PubMed2005

Specifying race-ethnic differences in risk for psychiatric disorder in a USA national sample.

BACKGROUND: Epidemiological studies have found lower than expected prevalence of psychiatric disorders among disadvantaged race-ethnic minority groups in the USA. Recent research shows that this is due entirely to reduced lifetime risk of disorders, as opposed to persistence. Specification of race-ethnic differences with respect to clinical and social characteristics can help identify the protective factors that lead to lower lifetime risk among disadvantaged minority groups. METHOD: Data on 5424 Hispanics, non-Hispanic Blacks, and non-Hispanic Whites came from the National Comorbidity Survey Replication, a nationally representative survey conducted with the World Mental Health version of the Composite International Diagnostic Interview. Race-ethnic differences in risk of disorders were compared across specific diagnoses, ages of onset, cohorts and levels of education. RESULTS: Both minority groups had lower risk for common internalizing disorders: depression, generalized anxiety disorder, and social phobia. In addition, Hispanics had lower risk for dysthymia, oppositional-defiant disorder and attention deficit hyperactivity disorder; non-Hispanic Blacks had lower risk for panic disorder, substance use disorders and early-onset impulse control disorders. Lower risk among Hispanics, relative to non-Hispanic Whites, was found only among the younger cohort (age<or=43 years). Lower risk among minorities was more pronounced at lower levels of education. CONCLUSION: The pattern of race-ethnic differences in risk for psychiatric disorders suggests the presence of protective factors that originate in childhood and have generalized effects on internalizing disorders. For Hispanics, but not for non-Hispanic Blacks, the influence of these protective factors has emerged only recently.

Adolescent↗

PubMed2005

The prevalence and correlates of nonaffective psychosis in the National Comorbidity Survey Replication (NCS-R).

BACKGROUND: To estimate the prevalence and correlates of clinician-diagnosed DSM-IV nonaffective psychosis (NAP) in a national household survey. METHODS: Data came from the United States National Comorbidity Survey Replication (NCS-R). A screen for NAP was followed by blinded sub-sample clinical reappraisal interviews. Logistic regression was used to impute clinical diagnoses to respondents who were not re-interviewed. The method of Multiple Imputation (MI) was used to estimate prevalence and correlates. RESULTS: Clinician-diagnosed NAP was well predicted by the screen (area under the curve [AUC] = .80). The MI prevalence estimate of NAP (standard error in parentheses) is 5.0 (2.6) per 1000 population lifetime and 3.0 (2.2) per 1000 past 12 months. The vast majority (79.4%) of lifetime and 12-month (63.7%) cases met criteria for other DSM-IV hierarchy-free disorders. Fifty-eight percent of 12-month cases were in treatment, most in the mental health specialty sector. CONCLUSIONS: The screen for NAP in the NCS-R greatly improved on previous epidemiological surveys in reducing false positives, but coding of open-ended screening scale responses was still needed to achieve accurate prediction. The lower prevalence estimate than in total-population incidence studies raises concerns that systematic nonresponse bias causes downward bias in survey prevalence estimates of NAP.

Adolescent↗

PubMed2005

A genome scan of neuroticism in nicotine dependent smokers.

Neuroticism is a personality factor that has consistently been demonstrated to be associated with anxiety, depression, and other "internalizing" disorders. We analyzed a genome scan for neuroticism on a sample of 129 sib-pair families (113 with a single sibling pair, 18 with multiple sibling pairs) containing a total of 201 possible sibling pairs, ascertained for concordance on nicotine dependence. Using Merlin-Regress, we replicated peaks for neuroticism described by prior studies, on chromosomes 1 and 11 with LOD scores of 2.52 and 1.97 (P-value of 0.003 and 0.0108) respectively, and have some evidence for a novel finding on chromosome 12 with a LOD of 2.85 (P-value of 0.0014).

Adult↗

PubMed2005

The structure of genetic and environmental risk factors for anxiety disorders in men and women.

BACKGROUND: The anxiety disorders exhibit high levels of lifetime comorbidity with one another. Understanding the underlying causes of this comorbidity can provide insight into the etiology of the disorders and inform classification and treatment. OBJECTIVE: To explain anxiety disorder comorbidity by examining the structure of the underlying genetic and environmental risk factors. DESIGN: Lifetime diagnoses for 6 anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, and situational phobia) were obtained during personal interviews from a population-based twin registry. Multivariate structural equation modeling that allowed for sex differences was performed. SETTING: General community sample. PARTICIPANTS: More than 5000 members of male-male and female-female twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. MAIN OUTCOME MEASURES: Parameter estimates for best-fitting model. RESULTS: The full model, which contained 2 common genetic, shared environmental, and unique environmental factors plus disorder-specific factors, could be constrained to equality across male and female study participants. In the best-fitting model, the genetic influences on anxiety were best explained by 2 additive genetic factors common across the disorders. The first loaded most strongly in generalized anxiety disorder, panic disorder, and agoraphobia, whereas the second loaded primarily in the 2 specific phobias. Social phobia was intermediate in that it was influenced by both genetic factors. A small role for shared environmental influences was observed owing to a single common factor that accounted for less than 12% of the total variance for any disorder. Unique environmental influences could be explained by a single common factor plus disorder-specific effects. CONCLUSIONS: The underlying structure of the genetic and environmental risk factors for the anxiety disorders is similar between men and women. Genes predispose to 2 broad groups of disorders dichotomized as panic-generalized-agoraphobic anxiety vs the specific phobias. The remaining associations between the disorders are largely explained by a unique environmental factor shared across the disorders and, to a lesser extent, a common shared environmental factor.

Adult↗

PubMed2005

The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication.

CONTEXT: Prior evidence from twin studies suggested genetic moderation of the depressogenic effects of stressful life events (SLEs). Can the specific genes involved in this effect be identified? OBJECTIVE: To replicate and extend a recent study that a functional variant in the serotonin transporter (5-HTT) might in part explain these findings. DESIGN: Characterizing risk for major depression and generalized anxiety syndrome in the last year as a function of 5-HTT genotype, sex, and the occurrence of SLEs and ratings of the SLE-associated level of threat. SETTING: A population-based sample of adult twins. PARTICIPANTS: Five hundred forty-nine male and female twins with a mean age at participation of 34.9 years (SD 9.1). MAIN OUTCOME MEASURE: Episodes of major depression and generalized anxiety syndrome in the last year with onset measured to the nearest month. RESULTS: Individuals with 2 short (S) alleles at the 5-HTT locus were more sensitive to the depressogenic effects of all SLEs than were those with 1 or 2 long (L) alleles. When level of SLE-associated threat was examined, the interaction between genotype and SLE resulted from an increased sensitivity of SS individuals to the depressogenic effects of common low-threat events. These events had little impact on risk for those possessing the SL and LL genotypes. The 5-HTT genotype did not modify the effects of SLEs on risk for generalized anxiety syndrome. CONCLUSION: Variation at the 5-HTT moderates the sensitivity of individuals to the depressogenic effects of SLEs largely by producing, in SS individuals, an increased sensitivity to the impact of mild stressors. Replication of these intriguing results is needed.

Adult↗

PubMed2005

Endorsement frequencies and factor structure of DSM-III-R and DSM-IV Generalized Anxiety Disorder symptoms in women: implications for future research, classification, clinical practice and comorbidity.

UNLABELLED: We investigated dimensions of liability to Generalized Anxiety Disorder (GAD) and whether evidence exists for distinct pathological versus normal clusters in the population. Structured interviews were administered to a general population sample of 2,163 female twins in a cross-sectional design. Endorsement rates were estimated using full information maximum likelihood factor analyses of the DSM-III-R and DSM-IV GAD symptoms, which provides appropriate treatment of the stem-probe structure of the clinical interview. Endorsement rates were highest for symptoms retained in DSM-IV. For both DSM-III-R and DSM-IV, a two-factor model fit the data better than a single-factor model. There was no evidence for non-normality in the liability to GAD. For DSM-III-R, autonomic symptoms loaded on a factor with panic disorder, while fatiguability, difficulty concentrating and hypervigilance loaded on a factor with major depression. For DSM-IV, all items loaded on one factor, and muscle tension also loaded on a second. Major depression, panic, phobias and alcohol dependence diagnoses also loaded on the first factor. CONCLUSIONS: Future research involving structured interviews should take into account the stem-and-probe format and focus on common factors rather than separate disorders; GAD is not a unidimensional construct and pathological anxiety may differ only quantitatively from normal anxiety.

Adolescent↗