Biomedical subjects

K S Kendler

Publications and source records attributed to K S Kendler.

At least 19 recordsLinked to original sources

PubMed2006

Interleukin 3 and schizophrenia: the impact of sex and family history.

Chromosome 5q21-33 has been implicated in harboring risk genes for schizophrenia. In this paper, we report evidence that multiple single nucleotide polymorphisms in and around interleukin 3 (IL3) are associated with the disease in the Irish Study of High-Density Schizophrenia Families (ISHDSF), the Irish Case-Control Study of Schizophrenia (ICCSS) and the Irish Trio Study of Schizophrenia (ITRIO). The associations are sex-specific and depend on the family history (FH) of schizophrenia. In all three samples, rs31400 shows female-specific and FH-dependent associations (P=0.0062, 0.0647 and 0.0284 for the ISHDSF, ICCSS and ITRIO, respectively). Several markers have similar associations in one or two of the three samples. In haplotype analyses, identical risk and protective haplotypes are identified in the ISHDSF and ITRIO samples in several multimarker combinations. For ICCSS, the same haplotypes are implicated; however, the risk haplotypes observed in the family samples become protective. Several significant markers, rs440970, rs31400 and rs2069803, are located in and around known estrogen response elements, promoter and enhancer of the IL3 gene. They may explain the sex-specific associations and be functional for the expression of IL3 gene.

Case-Control Studies↗

PubMed2006

Catechol-O-methyltransferase and the clinical features of psychosis.

A functional polymorphism (Val-158-Met) at the Catechol-O-methyltransferase (COMT) locus has been identified as a potential etiological factor in schizophrenia. Yet the association has not been convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To clarify the putative association, we performed an exploratory analysis to test for association between COMT and five psychosis symptom scales. These were derived through factor analysis of the Operational Criteria Checklist for Psychiatric Illness. Our sample was the Irish Study of High Density Schizophrenia Families, a large collection consisting of 268 multiplex families. This sample has previously shown a small but significant effect of the COMT Val allele in conferring risk for schizophrenia. We tested for preferential transmission of COMT alleles from parent to affected offspring (n = 749) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression). Significant overtransmission of the Val allele was found for mania (P < 0.05) and depression (P = 0.01) scales. Examination of odds ratios (ORs) revealed a heterogeneous effect of COMT, whereby it had no effect on Negative Symptoms, but largest impact on Depression (OR = 1.4). These results suggest a modest affective vulnerability conferred by this allele in psychosis, but will require replication.

Catechol O-Methyltransferase↗

PubMed2006

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

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

Alcohol-Related Disorders↗

PubMed2006

Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism.

Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six single-nucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.

Anxiety Disorders↗

PubMed2006

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

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

Aged↗

PubMed2005

Illicit drug use and abuse/dependence: modeling of two-stage variables using the CCC approach.

Drug use and abuse/dependence are stages of a complex drug habit. Most genetically informative models that are fit to twin data examine drug use and abuse/dependence independent of each other. This poses an interesting question: for a multistage process, how can we partition the factors influencing each stage specifically from the factors that are common to both stages? We used a causal-common-contingent (CCC) model to partition the common and specific influences on drug use and abuse/dependence. Data on use and abuse/dependence of cannabis, cocaine, sedatives, stimulants and any illicit drug was obtained from male and female twin pairs. CCC models were tested individually for each sex and in a sex-equal model. Our results suggest that there is evidence for additive genetic, shared environmental and unique environmental influences that are common to illicit drug use and abuse/dependence. Furthermore, we found substantial evidence for factors that were specific to abuse/dependence. Finally, sexes could be equated for all illicit drugs. The findings of this study emphasize the need for models that can partition the sources of individual differences into common and stage-specific influences.

Adult↗

PubMed2005

Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework.

Schizophrenia has long been thought to be clinically heterogeneous. A range of studies suggests that this is due to genetic heterogeneity. Some clinical features, such as negative symptoms, are associated with a greater risk of illness in relatives. Affected sibling pairs are correlated for clinical and course features as well as subforms of illness, and twin studies suggest that this is due to genetic factors. This is further supported by findings that subjects from families linked to some chromosomal regions may differ clinically from those from unlinked families. Moreover, some genes may affect clinical features without altering susceptibility (ie are modifier genes). High-risk genotypes may have quantitative, rather than categorical effects, and may influence milder or subclinical phenotypes. Another recent finding is that nonpsychotic relatives may have personality features that resemble those of their affected relatives. These findings taken together suggest that there may be several classes of gene action in schizophrenia: some genes may influence susceptibility only, others may influence clinical features only, and still others may have a mixed effect. Furthermore, subsets of these classes may affect personality and other traits in nonpsychotic relatives. Understanding these classes of gene action may help guide the design of linkage and association studies that have increased power. We describe five classes of genes and their predictions of the outcomes of family, twin, and several types of linkage studies. We go on to explore how these predictions can in turn be used to aid in the design of linkage studies.

Genetic Linkage↗

PubMed2004

Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study.

Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.

Alleles↗

PubMed2004

The prediction of thoughts of death or self-harm in a population-based sample of female twins.

BACKGROUND: Although suicide is a leading cause of death, few studies have attempted to predict suicidal ideation prospectively using epidemiological samples or multivariate methods. METHOD: Discrete-time event history analysis was used to model the onset of thoughts of death or self-harm (TD/SH) in a population-based sample of female twins (N=2164) using variables from the demographic, psychopathological, childhood adversity, personality and life event domains. Univariate, multivariate-within domain and multivariate-across domain regression analyses were performed. RESULTS: Most variables predicted TD/SH in the univariate analyses. However, the only variables to predict TD/SH independently were obsessive symptoms, childhood sexual abuse, rural residence, unemployment, older age, lifetime history of cocaine misuse and low levels of education, personal religious devotion and altruism, as well as divorce/separation, loss of confidant, assault, job loss and financial problems in the previous month. This final model explained 16% of the variance in TD/SH. Lifetime histories of major depression, panic disorder and alcohol misuse had no significant independent effect. CONCLUSIONS: Many variables, from all five domains of risk factors, are associated with the risk of TD/SH, but many of these effects may be mediated by other risk factors. Proximal life events and psychopathology may have more independent effects than other domains. The overall ability of these risk factors to predict TD/SH is modest. We cannot rule out that differences between these analyses and previous reports were due to our use of TD/SH as the dependent variable instead of thoughts of committing suicide per se.

Adult↗

PubMed2004

Multicenter linkage study of schizophrenia loci on chromosome 22q.

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.

Chromosome Mapping↗

PubMed2004

Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families.

The enzyme catechol-o-methyltransferase (COMT) transfers a methyl group from adenosylmethionine to catecholamines including the neurotransmitters dopamine, epinephrine and norepinephrine. This methylation results in the degradation of catecholamines. The involvement of the COMT gene in the metabolic pathway of these neurotransmitters has made it an attractive candidate gene for many psychiatric disorders. In this article, we reported our study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia. Three single nucleotide polymorphisms (SNPs) were genotyped for the 274 such families and within-family transmission disequilibrium tests were performed. SNP rs4680, which is the functional Val/Met polymorphism, showed modest association with the disease by the TRANSMIT, FBAT and PDT programs, while the other two SNPs were negative. These SNPs showed lower level of LDs with each other in the Irish subjects than in Ashkenazi Jews. Haplotype analysis indicated that a haplotype, haplotype A-G-A for SNPs rs737865-rs4680-rs165599, was preferentially transmitted to the affected subjects. This was different from the reported G-G-G haplotype found in Ashkenazi Jews, but both haplotypes shared the Val allele. We concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects.

Alleles↗

PubMed2004

No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF).

The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.

Chromosome Mapping↗

PubMed2004

Linkage analysis of smoking initiation and quantity in Dutch sibling pairs.

The heritability of smoking initiation (SI) and number of cigarettes smoked (NC) was determined in 3657 Dutch twin pairs. For SI a heritability of 36% was found and for NC of 51%. Both SI and NC were also significantly influenced by environmental factors shared by family members. The etiological factors that influence these traits partly overlap. Linkage analyses were performed on data of 536 DZ twins and siblings from 192 families, forming 592 sibling pairs. Results suggested QTLs on chromosome 6 (LOD=3.05) and chromosome 14 (LOD=1.66) for SI and on chromosome 3 (LOD=1.98) for NC. Strikingly, on chromosome 10 a peak was found in the same region for both SI (LOD=1.92) and for NC (LOD=2.29) which may partly explain the overlapping etiological factors for SI and NC.

Chromosome Mapping↗

PubMed2003

Fatigue in a community sample of twins.

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

Adult↗

PubMed2003

Interpersonal dependence and major depression: aetiological inter-relationship and gender differences.

BACKGROUND: Although prior research has demonstrated a strong association between interpersonal dependency (IPD) levels and risk for major depression (MD), the possible aetiological explanations of this association as well as any gender differences in the IPD-MD relationship need further clarification. METHOD: Population-based twin samples (N = 7174) were interviewed in multiple waves to assess IPD and MD as part of a larger twin study. IPD levels were assessed using the Interpersonal Dependency Inventory while MD diagnoses were derived from the SCID. Cox proportional hazard models and multiple regression techniques were utilized. RESULTS: IPD was strongly associated with a risk for lifetime MD. Pre-morbid IPD scores were predictive of future onsets of MD while experiencing a MD episode was also associated with a significant rise in IPD levels. While females had higher IPD scores, IPD scores were more significantly associated with risk for lifetime MD in males. Controlling for the level of IPD substantially reduced the observed association between gender and risk for MD. CONCLUSION: The strong association observed between IPD and risk for MD results largely from IPD being a risk factor for MD, but state effects of MD on IPD also contribute. IPD scores in males were more predictive of lifetime MD than for females. The higher levels of IPD in women than in men may contribute meaningfully to the sex differences in risk for MD.

Major Depressive Disorder↗

PubMed2003

Does the level of family dysfunction moderate the impact of genetic factors on the personality trait of neuroticism?

BACKGROUND: While the family environment can directly influence later risk for psychopathology, dysfunction in the family of origin may also moderate the impact of genetic factors on liability for psychiatric disorders. Can a similar pattern be seen for the personality trait of Neuroticism (N)-which is a risk factor for many psychiatric conditions? METHOD: Our sample of 957 complete female-female twin pairs from a population-based register had measures of self-reported N and multiple reporters (twin, co-twin, mother, father) for family dysfunction (FD). Statistical analysis was conducted by traditional regression analysis and a moderator structural equation twin model operationalized in the computer program Mx. RESULTS: Dividing the sample into quartiles based on increasing levels of FD, the mean of N increased substantially while correlations of N in monozygotic (MZ) and dizygotic (DZ) twins were relatively constant. Regression analyses did not suggest greater twin resemblance for N with increasing levels of FD. The best-fit structural equation model was the standard un-moderated model in which the proportion of variance in N due to genetic (39%) and unique environmental effects (61%) remained constant across values of FD. CONCLUSIONS: Although a false-negative result due to limited power cannot be excluded, these analyses do not support the hypothesis that FD moderates the impact of genetic factors on levels of N.

Family Health↗

PubMed2003

Personality and the experience of environmental adversity.

BACKGROUND: While psychiatric epidemiology often focuses on the causal relationship between environmental adversity and the individual (e.g. environment to person), individuals probably make important contributions to the quality of their environments (person to environment). METHOD: In a population based sample of > 7000 male and female adult twins, we examined the relationship between the personality trait of neuroticism (N) and the occurrence of stressful life events (SLEs) and the quality of interpersonal relationships (IPR). We compared the magnitude of the prediction of twin 1's self-reported SLEs and IPR from: (i) twin 1's self-reported N; (ii) twin 2's report of twin 1's N; and (iii) twin 2's report of twin 2's N in monozygotic pairs. RESULTS: In our entire sample, self-report N significantly predicted the occurrence of most SLEs and all dimensions of IPR. Using the co-twin's report of N produced associations that were of the same magnitude for SLEs and modestly weaker for IPR. In monozygotic pairs, the level of N in one twin predicted SLEs and IPR in the co-twin at levels similar to those found for the co-twin's report of N. Repeating these analyses with a prospective subsample produced similar results. CONCLUSION: An individual's personality in adulthood plays a significant role in influencing exposure to some forms of environmental adversity and this association is not the result of reporting bias. Furthermore, this relationship is largely mediated by a common set of familial factors that predispose both to a 'difficult' temperament and to environmental adversity. Developmental models of psychiatric illness should adopt an interactionist view of individuals and their environment (person and environment).

Adaptation, Psychological↗

PubMed2003

The effects of anxiety, substance use and conduct disorders on risk of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is highly co-morbid with other Axis I disorders, which commonly precede its onset. We sought to determine the level and periods of risk for MDD posed by prior or co-occurring psychiatric disorders. METHOD: Using retrospective data from a longitudinal, population-based sample of 2926 male and 1929 female adult twin subjects, we predicted the hazard rates for MDD from a Cox proportional hazards model with same-year or prior onsets of co-morbid Axis I disorders as time-dependent covariates. RESULTS: All axis I disorders studied (generalized anxiety disorder, panic disorder, phobia, alcohol dependence, psychoactive substance use disorders and conduct disorder) significantly predicted increased risk for developing MDD. The highest hazard rates occurred for MDD onsets that co-occurred with those of the co-morbid disorder. However, the risk for onset of MDD subsequent to that of prior disorders is also significantly increased and remains relatively unchanged over time. Although the risk for onset of MDD is significantly higher in women than men, this was not explained by gender differences in prior disorder prevalence or increased sensitivity in women to the effects of prior disorders on risk for depression. CONCLUSIONS: Prior psychiatric disorders are significant risk factors for the development of MDD, independent of the length of the intervening period between the onset of the first disorder and that of MDD.

Adult↗