Biomedical subjects

Kenneth S Kendler

Publications and source records attributed to Kenneth S Kendler.

At least 19 recordsLinked to original sources

PubMed2018

The Role of Emergence in Genetically Informed Relationships Research: A Methodological Analysis.

This paper provides a critical analysis of genetically informed research on relationships, with an emphasis on relationships among unrelated individuals (e.g., spouses). To date, research in this area has used traditional behavioral genetic frameworks to either partition the variance in relationship-related outcomes into genetic and environmental components, or to examine gene-environment interplay between relationship factors and other outcomes. However, this conventional approach is at odds with the long-standing understanding from the field of relationship science that both partners' characteristics matter when predicting shared outcomes-that is, outcomes that are emergent. We examine briefly the philosophical concept of emergence, and discuss ways to model dyadic outcomes in genetically informed relationships research. We also review the related topic of social genetic effects, which refer to the influence of a social partner's genotype on a proband's phenotype. A genetically informed dyadic perspective has potentially important consequences for our understanding of the pathways from genotype→shared or individual-level phenotypes, and more fully recognizes the complexity of how genetic and social/environmental factors come together to influence human behavior.

Genetics, Behavioral↗

PubMed2007

Association between the 5q31.1 gene neurogenin1 and schizophrenia.

Multiple lines of evidence suggest that schizophrenia results from aberrant neurodevelopment. The neurogenin1 gene (neurog1) consists of a single 1,666 bp exon that encodes a basic helix-loop-helix (bHLH) transcription factor that causes neuronal differentiation and induces cortical and glutamatergic differentiation programs. Because of its function and its location in 5q31.1, which has been linked to schizophrenia in multiple samples, we tested it for association with the disorder. We sequenced neurog1 in 25 affected subjects from the Irish Study of High-Density Schizophrenia Families. We observed a 5'-UTR SNP at position -60, already present in databases as rs8192558, and tested it along with rs2344485, rs8192559, and rs2344484. Narrow, intermediate, and broad diagnostic definitions were used. The major alleles of rs8192558 and rs2344484 were over-transmitted to affected subjects using both Pedigree Disequilibrium Test (PDT) (0.01 < or = P < or = 0.06) and FBAT (0.02 < or = P < or = 0.07). A haplotype consisting of the major alleles of all four SNPs was significantly over-transmitted in FBAT to the broad definition (P = 0.049), with trend significance to the narrow and intermediate definitions, and with trend significance in PDT. In confirmatory tests using 657 cases and 411 controls, this haplotype was slightly but not significantly over-represented in cases (81% vs. 77%, P = 0.21). These results, along with a priori evidence for the involvement of neurog1 in neurodevelopment, suggest that variants in neurog1 might have a small effect on susceptibility to schizophrenia. This gene should be tested in additional and larger samples.

Basic Helix-Loop-Helix Proteins↗

PubMed2007

The heritability of cluster A personality disorders assessed by both personal interview and questionnaire.

BACKGROUND: Personality disorders (PDs) as assessed by questionnaires and personal interviews are heritable. However, we know neither how much unreliability of measurement impacts on heritability estimates nor whether the genetic and environmental risk factors assessed by these two methods are the same. We wish to know whether the same set of PD vulnerability factors are assessed by these two methods. METHOD: A total of 3334 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel (NIPHTP) completed a questionnaire containing 91 PD items. One to 6 years later, 1386 of these pairs were interviewed with the Structured Interview for DSM-IV Personality (SIDP-IV). Self-report items predicting interview results were selected by regression. Measurement models were fitted using Mx. RESULTS: In the best-fit models, the latent liabilities to paranoid personality disorder (PPD), schizoid personality disorder (SPD) and schizotypal personality disorder (STPD) were all highly heritable with no evidence of shared environmental effects. For PPD and STPD, only unique environmental effects were specific to the interview measure whereas both environmental and genetic effects were found to be specific to the questionnaire assessment. For SPD, the best-fit model contained genetic and environmental effects specific to both forms of assessment. CONCLUSIONS: The latent liabilities to the cluster A PDs are highly heritable but are assessed by current methods with only moderate reliability. The personal interviews assessed the genetic risk for the latent trait with excellent specificity for PPD and STPD and good specificity for SPD. However, for all three PDs, the questionnaires were less specific, also indexing an independent set of genetic risk factors.

Adult↗

PubMed2007

A multivariate analysis of neuroanatomic relationships in a genetically informative pediatric sample.

An important component of brain mapping is an understanding of the relationships between neuroanatomic structures, as well as the nature of shared causal factors. Prior twin studies have demonstrated that much of individual differences in human anatomy are caused by genetic differences, but information is limited on whether different structures share common genetic factors. We performed a multivariate statistical genetic analysis on volumetric MRI measures (cerebrum, cerebellum, lateral ventricles, corpus callosum, thalamus, and basal ganglia) from a pediatric sample of 326 twins and 158 singletons. Our results suggest that the great majority of variability in cerebrum, cerebellum, thalamus and basal ganglia is determined by a single genetic factor. Though most (75%) of the variability in corpus callosum was explained by additive genetic effects these were largely independent of other structures. We also observed relatively small but significant environmental effects common to multiple neuroanatomic regions, particularly between thalamus, basal ganglia, and lateral ventricles. These findings are concordant with prior volumetric twin studies and support radial models of brain evolution.

Adolescent↗

PubMed2006

Genetic influences on measures of the environment: a systematic review.

BACKGROUND: Traditional models of psychiatric epidemiology often assume that the relationship between individuals and their environment is unidirectional, from environment to person. Accumulating evidence from developmental and genetic studies has made this perspective increasingly untenable. METHOD: Literature search using Medline, PsycINFO, article references and contact with experts to identify all papers examining the heritability of measures of environments of relevance to psychiatry/psychology. RESULTS: We identified 55 independent studies organized into seven categories: general and specific stressful life events (SLEs), parenting as reported by child, parenting reported by parent, family environment, social support, peer interactions, and marital quality. Thirty-five environmental measures in these categories were examined by at least two studies and produced weighted heritability estimates ranging from 7% to 39%, with most falling between 15% and 35%. The weighted heritability for all environmental measures in all studies was 27%. The weighted heritability for environmental measures by rating method was: self-report 29%, informant report 26%, and direct rater or videotape observation (typically examining 10 min of behavior) 14%. CONCLUSION: Genetic influences on measures of the environment are pervasive in extent and modest to moderate in impact. These findings largely reflect 'actual behavior' rather than 'only perceptions'. Etiologic models for psychiatric illness need to account for the non-trivial influences of genetic factors on environmental experiences.

Child↗

PubMed2006

Genetic and environmental influences on dimensional representations of DSM-IV cluster C personality disorders: a population-based multivariate twin study.

BACKGROUND: The DSM-IV cluster C Axis II disorders include avoidant (AVPD), dependent (DEPD) and obsessive-compulsive (OCPD) personality disorders. We aimed to estimate the genetic and environmental influences on dimensional representations of these disorders and examine the validity of the cluster C construct by determining to what extent common familial factors influence the individual PDs. METHOD: PDs were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV) in a sample of 1386 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel (NIPHTP). A single-factor independent pathway multivariate model was applied to the number of endorsed criteria for the three cluster C disorders, using the statistical modeling program Mx. RESULTS: The best-fitting model included genetic and unique environmental factors only, and equated parameters for males and females. Heritability ranged from 27% to 35%. The proportion of genetic variance explained by a common factor was 83, 48 and 15% respectively for AVPD, DEPD and OCPD. Common genetic and environmental factors accounted for 54% and 64% respectively of the variance in AVPD and DEPD but only 11% of the variance in OCPD. CONCLUSION: Cluster C PDs are moderately heritable. No evidence was found for shared environmental or sex effects. Common genetic and individual environmental factors account for a substantial proportion of the variance in AVPD and DEPD. However, OCPD appears to be largely etiologically distinct from the other two PDs. The results do not support the validity of the DSM-IV cluster C construct in its present form.

Adult↗

PubMed2006

The sources of co-morbidity between major depression and generalized anxiety disorder in a Swedish national twin sample.

BACKGROUND: Prior studies report high levels of co-morbidity between major depression (MD) and generalized anxiety disorder (GAD) and suggest that these disorders are closely related genetically. The personality trait of neuroticism (N) is substantially correlated with risk for MD and GAD. METHOD: Bivariate twin models were applied to lifetime diagnoses of modified DSM-IV diagnosis of MD and GAD obtained at personal interview in 1998-2003 with 37296 twins from the population-based Swedish Twin Registry. A trivariate Cholesky model with N, MD and GAD was applied to a subset (23280 members of same-sex twin pairs) who completed a self-report questionnaire assessing N in 1972-1973. RESULTS: In the best-fit bivariate model, the genetic correlation between MD and GAD was estimated at +1.00 in females and +0.74 in males. Individual-specific environmental factors were also shared between the two disorders with an estimated correlation of +0.59 in males and +0.36 in females. In the best-fit trivariate Cholesky model, genetic factors indexed by N impacted equally on risk for MD and GAD in males and females. However, in both sexes, genetic risk factors indexed by N contributed only around 25% to the genetic correlation between MD and GAD. CONCLUSION: Genetic risk factors for lifetime MD and GAD are strongly correlated, with higher correlations in women than in men. Although genetic risk factors indexed by the personality trait of N contribute substantially to risk for both MD and GAD, the majority of genetic covariance between the two disorders results from factors not shared with N.

Adult↗

PubMed2006

Genetic and environmental contributions to depressive personality disorder in a population-based sample of Norwegian twins.

BACKGROUND: Depressive personality disorder (DPD) was introduced in DSM-IV as a new category requiring further study. The aim of this study was to estimate genetic and environmental contributions to DPD in a population-based twin sample, and include data on criteria performance, prevalence and diagnostic overlap. METHODS: Axis I and Axis II diagnoses were obtained by structured interviews in a population-based sample of 2794 young adult twins. Statistical analyses included correlation and factor analysis based on polychoric correlation coefficients, and diagnostic overlap applying adjusted odds ratios. Contributions from additive genetic and common and unique environmental influences to the liability to DPD were computed using structural equation modelling, applying a multiple threshold variable. RESULTS: Liability to DPD could best be explained by additive genetic and unique environmental factors, with heritability estimates of 49% (95% CI 0.41-0.57) in females and 25% (95% CI 0.12-0.40) in males. The best-fitting model indicated that some of the genes contributing to DPD differ between men and women. Chronbach's alpha was 0.87. 2.0% of participants fulfilled the criteria for DPD, and overlap was most pronounced for dysthymic disorder and avoidant personality disorder. LIMITATIONS: Low prevalence rates and subsequent inclusion of subthreshold criteria could have influenced parameter estimates, especially in males. CONCLUSIONS: DPD was almost twice as heritable in females as in males, comparable to previous studies on major depression. The proposed criteria showed good measurement properties, and DPD was not completely subsumed within any other disorder.

Adult↗

PubMed2006

Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia.

Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density Schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes.

Chromosomes, Human, Pair 5↗

PubMed2006

Dimensional representations of DSM-IV cluster A personality disorders in a population-based sample of Norwegian twins: a multivariate study.

BACKGROUND: The 'odd' or 'Cluster A' personality disorders (PDs) - paranoid, schizoid and schizotypal PDs - were created in DSM-III with little empirical foundation. We have examined the relationship between the genetic and environmental risk factors for dimensional representations of these three personality disorders. METHOD: These personality disorders were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV) in 1386 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel. Using Mx, a single-factor independent pathway twin model was fitted to the number of endorsed criteria for the three disorders. RESULTS: The best-fit model included genetic and unique environmental common factors and genetic and unique environmental effects specific to each personality disorder. Total heritability was modest for these personality disorders and ranged from 21% to 28%. Loadings on the common genetic and unique environmental factors were substantially higher for schizotypal than for paranoid or schizoid PD. The proportion of genetic liability shared with all Cluster A disorders was estimated at 100, 43 and 26% respectively for schizotypal, paranoid and schizoid PDs. CONCLUSION: In support of the validity of the Cluster A construct, dimensional representations of schizotypal, paranoid and schizoid PD are all modestly heritable and share a portion of their genetic and environmental risk factors. No evidence was found for shared environmental or sex effects for these PDs. Schizotypal PD most closely reflects the genetic and environmental liability common to all three Cluster A disorders. These results should be interpreted in the context of the limited power of this sample.

Adult↗

PubMed2006

Caffeine intake, toxicity and dependence and lifetime risk for psychiatric and substance use disorders: an epidemiologic and co-twin control analysis.

BACKGROUND: Although caffeine is the most commonly used psychoactive substance and often produces symptoms of toxicity and dependence, little is known, especially in community samples, about the association between caffeine use, toxicity and dependence and risk for common psychiatric and substance use disorders. METHOD: Assessments of lifetime maximal caffeine use and symptoms of caffeine toxicity and dependence were available on over 3600 adult twins ascertained from the population-based Virginia Twin Registry. Lifetime histories of major depression (MD), generalized anxiety disorder (GAD) and panic disorder, alcohol dependence, adult antisocial behavior and cannabis and cocaine abuse/dependence were obtained at personal interview. Logistic regression analyses in the entire sample and within monozygotic (MZ) twin pairs were conducted in SAS. RESULTS: In the entire sample, measures of maximal caffeine use, heavy caffeine use, and caffeine-related toxicity and dependence were significantly and positively associated with all seven psychiatric and substance use disorders. However, within MZ twin pairs, controlling for genetic and family environmental factors, these associations, while positive, were all non-significant. These results were similar when excluding twins who denied regular caffeine use. CONCLUSIONS: Maximal lifetime caffeine intake and caffeine-associated toxicity and dependence are moderately associated with risk for a wide range of psychiatric and substance use disorders. Analyses of these relationships within MZ twin pairs suggest that most of the observed associations are not causal. Rather, familial factors, which are probably in part genetic, predispose to both caffeine intake, toxicity and dependence and the risk for a broad array of internalizing and externalizing disorders.

Adult↗

PubMed2006

The mu-opioid receptor gene and smoking initiation and nicotine dependence.

The gene encoding the mu-opioid receptor (OPRM1) is reported to be associated with a range of substance dependence. Experiments in knockout mice indicate that the mu-opioid receptor may mediate reinforcing effects of nicotine. In humans, opioid antagonist naltrexone may reduce the reinforcing effects of tobacco smoking. Additionally, the OPRM1 gene is located in a region showing linkage to nicotine dependence. The OPRM1 is thus a plausible candidate gene for smoking behavior. To investigate whether OPRM1 contributes to the susceptibility of smoking initiation and nicotine dependence, we genotyped 11 SNPs in the gene for 688 Caucasian subjects of lifetime smokers and nonsmokers. Three SNPs showed nominal significance for smoking initiation and one reached significance for nicotine dependence. The global test for three-marker (rs9479757-rs2075572-rs10485057) haplotypes was significant for smoking initiation (p = 0.0022). The same three-marker haplotype test was marginal (p = 0.0514) for nicotine dependence. These results suggest that OPRM1 may be involved in smoking initiation and nicotine dependence.

Journal Article↗

PubMed2006

Genetic and cultural transmission of smoking initiation: an extended twin kinship model.

BACKGROUND: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a significant role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent-offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. METHODS: We examined the role of genetic and environmental factors for smoking initiation using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission. A dichotomous lifetime smoking measure was obtained from twins and relatives in the Virginia 30,000 sample. RESULTS: Results demonstrate that both genetic and environmental factors play a significant role in the liability to smoking initiation. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission and resulting genotype-environment covariance. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent-offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (i) age x gene interaction, and (ii) social homogamy. Neither mechanism provided a significantly better explanation of the data, although age regression was significant. CONCLUSIONS: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on smoking initiation.

Aged↗

PubMed2006

Extensions to the modeling of initiation and progression: applications to substance use and abuse.

Twin data can provide valuable insight into the relationship between the stages of phenomena such as disease or substance abuse. Initiation of substance use may be caused by factors that are the same as, partially shared with, or completely independent of those that cause progression from use to abuse. Comparison of rates of progression among the cotwins of twins who do vs. do not initiate provides indirect information about the relationship between initiation and progression. Existing models for this relationship have been difficult to extend because they are usually expressed in terms of explicit integrals. In this paper, the problem is overcome by regarding the analysis of twin data on initiation and progression as a special case of missing data, in which individuals who do not initiate are regarded as having missing data on progression measures. Using the general framework for the analysis of ordinal data with missing values available in Mx makes extensions that include other variables much easier. The effects of continuous covariates such as age on initiation and progression becomes simple. Also facilitated are the examination of initiation and progression in two or more substances, and transition models with two or more steps. The methods are illustrated with data on the effects of cohort on liability to cannabis use and abuse, bivariate analysis of tobacco use and dependence and cannabis use and abuse, and the relationships between initiation of smoking, regular smoking and nicotine dependence. Other suitable applications include the relationship between symptoms and diagnosis, such as fears and the progression to phobia.

Age Factors↗

PubMed2006

The temporal relationship of the onsets of alcohol dependence and major depression: using a genetically informative study design.

BACKGROUND: Although alcohol dependence (AD) and major depression (MD) are highly co-morbid, their causal relationship is unclear. In this longitudinal study, we used a genetically informative population-based twin sample to examine the age-at-onset distributions and the temporal relationship of AD and MD. METHOD: Our sample included 7477 twins, whose diagnoses of AD and MD and age-at-onset information were obtained from structured interviews. Individual-level survival analyses were conducted based on 2603 monozygotic (MZ) twins, and co-twin diagnosis was included in models as an index of familiar liability to AD and MD. RESULTS: The age-at-onset distributions of AD and MD differed substantially. Most onsets of AD were in young adulthood, whereas MD had a flatter distribution across age. Most subjects, especially women, had an onset of MD preceding AD. Prior MD significantly affected risk for developing AD, and this risk decreased over time. By contrast, preceding AD had negligible effects on the risk for future MD. Familial risk was transmitted within disorders but there was little evidence of additional familial liability shared across disorders. CONCLUSIONS: Risk for developing AD was substantially increased by a prior episode of MD. The association was only partially accounted for by familial factors, providing support for a direct causal effect such as self-medication. The etiologic path from AD to MD was insignificant.

Adult↗

PubMed2006

Illicit psychoactive substance use, abuse and dependence in a population-based sample of Norwegian twins.

BACKGROUND: Prior population-based twin studies from two Anglophonic countries with relatively high rates of drug use - the USA and Australia - suggest that genetic factors contribute substantially to individual differences in the use, abuse and dependence of illicit psychoactive substances. Would these results replicate in Norway, a Nordic country with a low prevalence of illicit drug use? METHOD: Lifetime use, abuse and dependence of five illicit drug categories (cannabis, stimulants, opiates, cocaine and psychedelics) were assessed at personal interview in 1386 complete young adult twin pairs ascertained from the Norwegian Institute of Public Health Twin Panel. Twin model fitting was performed using the Mx statistical package on three phenotypes: any lifetime use, endorsement of at least one DSM-IV symptom of abuse or dependence, and meeting DSM-IV criteria for abuse or dependence. RESULTS: Significant lifetime use of illicit substances (defined as use 10 or more times) was reported by only 6.4% of the sample. Meaningful analyses were possible for use of any substance and each of the five substances individually, but for symptoms or a diagnosis of abuse/dependence meaningful analyses were possible only for any substance and cannabis. Full twin models uniformly found twin resemblance to be due largely or entirely to genetic factors. Best-fit models for all analyses included only genetic and individual-specific environmental effects with heritability estimates ranging from 58% to 81%. CONCLUSION: In accord with prior results from the USA and Australia, genetic factors appear to play an important role in the etiology of use and abuse/dependence of illicit drugs in Norway.

Diseases in Twins↗

PubMed2006

Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples.

BACKGROUND: Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. METHODS: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). RESULTS: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. CONCLUSIONS: Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Case-Control Studies↗

PubMed2006

The impact of generalized anxiety disorder and stressful life events on risk for major depressive episodes.

BACKGROUND: Both generalized anxiety disorder (GAD) and stressful life events (SLEs) are established risk factors for major depressive disorder, but no studies exist that examine the interrelationship of their impact on depressive onsets. In this study, we sought to analyze the joint effects of prior history of GAD and recent SLEs on risk for major depressive episodes, comparing these in men and women. METHOD: In a population-based sample of 8068 adult twins, Cox proportional hazard models were used to predict onsets of major depression from reported prior GAD and last-year SLEs rated on long-term contextual threat. RESULTS: For all levels of threat, prior GAD increases risk for depression, with a monotonic relationship between threat level and risk. While females without prior GAD consistently show higher depressive risk than males, this is no longer the case in subjects with prior GAD who have experienced SLEs. Rather, males appear to be more vulnerable to the depressogenic effects of both prior GAD and SLEs. CONCLUSION: The effects of prior GAD and SLEs jointly increase the risk of depression in both sexes, but disproportionately so in males.

Adult↗