Relationship of age of first drink to child behavioral problems and family psychopathology.

BACKGROUND: Studies have implicated a wide variety of variables as being associated with an early age of first drink (AFD). AFD in turn has been associated with a variety of negative outcomes in adolescence and early adulthood. This study is designed to quantify the contributions of these antecedent variables to prediction of AFD; in particular it will carefully examine the involvement of variables in four areas (child characteristics, family demographics, family psychopathology, and child behavior problems). METHODS: Using data from a multicenter study on alcoholism, we first investigated the differences between two groups of children (ages 7 to 17 years), one from families heavily loaded for alcohol dependence and the other from population controls. Second, a multidomain, multistep regression model using child characteristics, family demographics, family psychopathology, and child behavior problems was performed to determine significant contributors to predicted AFD. RESULTS: Five variables initially contributed to the prediction of AFD. These included gender, age at interview, the number of adult sibs with alcohol dependence, being held back a year in school, and conduct scale score. However, the number of conduct symptoms appeared to contain the contributions of gender and being held back a grade in school, and these two variables were subsequent removed from the model. The remaining three variables explained 45% of the model variance; age at interview accounted for 38.3%, conduct scale score accounted for 6.2%, and the number of alcohol-dependent adult sibs accounted for 0.5%. No family history measures of alcohol dependence or antisocial personality disorder were contributory to the prediction model for AFD. CONCLUSIONS: Both the "number of conduct symptoms" and the "number of adult sibs with alcohol dependence" are inversely associated with predicted AFD. The latter variable appears marginally predictive of AFD and suggests a condition in which the child's household, regardless of strength of family history of AD (or antisocial personality disorder), appears conducive to early drinking. Thus, child and environmental factors are stronger predictors of age of first drink than family history.

Whole genome linkage scan of recurrent depressive disorder from the depression network study.

Genome-wide linkage analysis was carried out in a sample of 497 sib pairs concordant for recurrent major depressive disorder (MDD). There was suggestive evidence for linkage on chromosome 1p36 where the LOD score for female-female pairs exceeded 3 (but reduced to 2.73 when corrected for multiple testing). The region includes a gene, MTHFR, that in previous studies has been associated with depressive symptoms. Two other regions, on chromosomes 12q23.3-q24.11 and 13q31.1-q31.3, showed evidence for linkage with a nominal P < 0.01. The 12q peak overlaps with a region previously implicated by linkage studies of unipolar and bipolar disorders and contains a gene, DAO, that has been associated with both bipolar disorder and schizophrenia. The 13q peak lies within a region previously linked strongly to panic disorder. A fourth modest peak with an LOD of greater than 1 on chromosome 15q lies within a region that showed genome-wide significant evidence of a recurrent depression locus in a previous sib-pair study. Both the 12q and the 15q findings remained significant at genome-wide level when the data from the present study and the previous reports were combined.

Long-term stability of alcohol and other substance dependence diagnoses and habitual smoking: an evaluation after 5 years.

CONTEXT: A major criterion to validate diagnoses is stability over time. OBJECTIVE: To examine the stability of several classification systems for lifetime diagnosis of alcohol dependence, to identify characteristics predicting stability of alcoholism, and to study stability of lifetime assessments of habitual smoking (1 pack per day for at least 6 months) and other drug dependence. DESIGN: Participants in the Collaborative Study on the Genetics of Alcoholism were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism and reevaluated 5 years later. Initial and follow-up interviews were available for 1728 individuals (641 index cases, 800 siblings, 287 controls) with lifetime diagnoses of alcohol dependence, other substance dependence (marijuana, cocaine, other stimulants, sedatives, opioids), or habitual smoking at first interview. The likelihood that an individual with a lifetime history of substance dependence or habitual smoking at the first interview retained this classification after 5 years was examined to assess stability of diagnosis. RESULTS: Stability of a lifetime diagnosis of alcohol dependence varied among the subject groups of index cases, siblings, and community-based controls. Alcohol dependence as defined by DSM-III-R criteria was highly stable in the index cases (90.5% women, 94.7% men) but much less stable in the community-based controls (27.5% women, 64.7% men). The most important characteristic associated with stability of diagnosis of alcohol dependence was severity, defined by the number of alcohol-related symptoms. Other DSM-III-R substance dependence disorders varied in the stability of diagnosis over a 5-year period. Lifetime history of habitual smoking was highly stable in all subject groups (96.0% overall). CONCLUSIONS: Stability of lifetime assessment of alcohol dependence varies depending on severity of illness. Severe cases of alcohol dependence are more likely to be stable, whereas general population cases of alcohol dependence are less likely to have stable diagnoses. The stability of diagnosis for other substance dependence varies from substance to substance.

Are there subgroups of bulimia nervosa based on comorbid psychiatric disorders?

OBJECTIVE: The current study sought to determine whether there are subtypes of bulimia nervosa (BN) differentiated by comorbid psychiatric disorders. METHOD: Data on comorbid psychiatric diagnoses in female relatives of probands and controls in the Collaborative Study of the Genetics of Alcoholism (COGA) who met criteria for BN (as outlined in the 3rd Rev. ed. of the Diagnostic and Statistical Manual of Mental Disorders) were analyzed using latent class analysis. Resulting latent classes were compared on a variety of variables related to impulsive behaviors and psychological functioning. RESULTS: The best-fitting solution, a two-class model, yielded one class (72%) characterized by substance dependence, depression, antisocial personality disorder (ASPD), and anxiety disorders, and another characterized by depression. The highly comorbid class had more suicidality, more daily smokers, sought help for emotional problems, and had lower Global Assessment of Functioning (GAF) scores compared with those in the comorbid depression only class. DISCUSSION: Latent class findings suggest the existence of two classes of BN differentiated by substance dependence, impulsive behaviors, and poorer psychological functioning.

A family study of alcohol dependence: coaggregation of multiple disorders in relatives of alcohol-dependent probands.

BACKGROUND: Alcohol dependence tends to aggregate within families. We analyzed data from the family collection of the Collaborative Study on the Genetics of Alcoholism to quantify familial aggregation using several different criterion sets. We also assessed the aggregation of other psychiatric disorders in the same sample to identify areas of possible shared genetic vulnerability. DESIGN: Age-corrected lifetime morbid risk was estimated in adult first-degree relatives of affected probands and control subjects for selected disorders. Diagnostic data were gathered by semistructured interview (the Semi-Structured Assessment for the Genetics of Alcoholism), family history, and medical records. Rates of illness were corrected by validating interview and family history reports against senior clinicians' all sources best estimate diagnoses. Sex, ethnicity, comorbidity, cohort effects, and site of ascertainment were also taken into account. RESULTS: Including data from 8296 relatives of alcoholic probands and 1654 controls, we report lifetime risk rates of 28.8% and 14.4% for DSM-IV alcohol dependence in relatives of probands and controls, respectively; respective rates were 37.0% and 20.5% for the less stringent DSM-III-R alcohol dependence, 20.9% and 9.7% for any DSM-III-R diagnosis of nonalcohol nonnicotine substance dependence, and 8.1% and 5.2% for antisocial personality disorder. Rates of specific substance dependence were markedly increased in relatives of alcohol-dependent probands for cocaine, marijuana, opiates, sedatives, stimulants, and tobacco. Aggregation was also seen for panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and major depression. CONCLUSIONS: The risk of alcohol dependence in relatives of probands compared with controls is increased about 2-fold. The aggregation of antisocial personality disorder, drug dependence, anxiety disorders, and mood disorders suggests common mechanisms for these disorders and alcohol dependence within some families. These data suggest new phenotypes for molecular genetic studies and alternative strategies for studying the heterogeneity of alcohol dependence.

The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study.

BACKGROUND: The Depression Network Study (DeNt) is a multicentre study designed to identify genes and/or loci linked to and/or associated with susceptibility to unipolar depression in Caucasian families. This study presents the method and socio-demographic details of the first 470 affected sibling pairs recruited from 8 different sites in Europe and the United States of America. METHODS: Probands fulfilling either the Diagnostic and Statistical Manual 4th edition (DSM-IV) or the International Classification of Diseases 10th edition (ICD-10) criteria for recurrent unipolar depression of moderate or severe degree and who had at least one similarly affected sibling were eligible for the study. Detailed clinical and psychological assessments were undertaken on all subjects including an interview using the Schedules for Clinical Assessment in Neuropsychiatry. Blood samples were collected from all participants to extract DNA for linkage analysis. RESULTS: The different sites used different recruitment strategies depending on local health care organisation but despite this there was remarkable similarity across sites for the subjects recruited. Although the Bonn site had significantly older subjects both for age of onset and age at interview, for the sample as a whole, subjects were interviewed in their mid-40s and had experienced the onset of their recurrent depression in their 20s. Preliminary genome screening was able to include 929 out of the 944 subjects (98.4%) typed at 932 autosomal and 544 X chromosome markers. CONCLUSIONS: This paper describes the methodology and the characteristics of the subjects from the 414 families included in the first wave of genotyping from the multi-site DeNT study. Ultimately the study aims to collect affected sibling pairs from approximately 1200 families.

Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome.

Several correlated phenotypes, alcohol dependence, major depressive syndrome, and an endophenotype of electrophysiological measurements, event-related oscillations (EROs), have demonstrated linkage on the long arm of chromosome 7. Recently, we reported both linkage and association between polymorphisms in the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) and EROs. In this study, we evaluated whether genetic variation in the CHRM2 gene is also a risk factor for the correlated clinical characteristics of alcoholism and depression. The CHRM2 gene contains a single coding exon and a large 5' untranslated region encoded by multiple exons that can be alternatively spliced. Families were recruited through an alcohol dependent proband, and multiplex pedigrees were selected for genetic analyses. We examined 11 single nucleotide polymorphisms (SNPs) spanning the CHRM2 gene in these families. Using the UNPHASED pedigree disequilibrium test (PDTPHASE), three SNPs (one in intron 4 and two in intron 5) showed highly significant association with alcoholism (P=0.004-0.007). Two SNPs (both in intron 4) were significantly associated with major depressive syndrome (P=0.004 and 0.017). Haplotype analyses revealed that the most common haplotype (>40% frequency), T-T-T (rs1824024-rs2061174-rs324650), was under-transmitted to affected individuals with alcohol dependence and major depressive syndrome. Different complementary haplotypes were over-transmitted in alcohol dependent and depressed individuals. These findings provide strong evidence that variants within or close to the CHRM2 locus influence risk for two common psychiatric disorders.

Linkage and linkage disequilibrium of evoked EEG oscillations with CHRM2 receptor gene polymorphisms: implications for human brain dynamics and cognition.

Event-related oscillations (ERO) offer an alternative theoretical and methodological approach to the analysis of event-related EEG responses. The P300 event-related potential (ERP) is elicited through the superposition of the delta (1-3 Hz) and theta (3-7 Hz) band oscillatory responses. The cholinergic neurotransmitter system has a key function in modulating excitatory post-synaptic potentials caused by glutamate, and therefore influences P300 generation and the underlying oscillatory responses. Here we report significant linkage and linkage disequilibrium between target case frontal theta band, visual evoked brain oscillations and a single nucleotide polymorphism (SNP) from the cholinergic muscarinic receptor gene (CHRM2) on chromosome 7. We also demonstrate significant linkage disequilibrium between CHRM2 SNPs and target case parietal delta band visual evoked oscillations (LD P<0.001). These findings were not observed for the equivalent non-target case data, suggesting a role for the CHRM2 gene in higher cognitive processing in humans.

Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees.

BACKGROUND: We have reported genetic linkage between bipolar disorder and markers on chromosome 6q16.3-22.1 in the National Institute of Mental Health Genetics Initiative wave 3 pedigrees. Here we test for: 1) robustness of the linkage to differing analysis methods, genotyping error, and gender-specific maps; 2) parent-of-origin effects; and 3) interaction with markers within the schizophrenia linkage region on chromosome 6p. METHODS: Members of 245 families ascertained through a sibling pair affected with bipolar I or schizoaffective-bipolar disorder were genotyped with 18 markers spanning chromosome 6. Nonparametric linkage analysis was performed. RESULTS: Linkage to 6q is robust to analysis method, gender-specific map differences, and genotyping error. The locus confers a 1.4-fold increased risk. Affected siblings share the maternal more often than the paternal chromosome (p =.006), which could reflect a maternal parent-of-origin effect. There is a positive correlation between family-specific linkage scores on 6q and those on 6p22.2 (r =.26; p <.0001). Linkage analysis for each locus conditioned on evidence of linkage to the other increases the evidence for linkage at both loci (p <.0005). Logarithm of the odds (LOD) scores increased from 2.26 to 5.42 on 6q and from.35 to 2.26 on 6p22.2. CONCLUSIONS: These results support linkage of bipolar disorder to 6q, uncover a maternal parent-of-origin effect, and demonstrate an interaction of this locus with one on chromosome 6p22.2, previously linked only to schizophrenia.

The Sib TDT adjusted for age of disease onset.

Since the Sib-TDT (Spielman & Ewens, 1998) ignores age of disease onset, there could be loss of power in detecting linkage. In this article, we propose an adjustment for age of onset using the Cox Proportional Hazard Model (Cox, 1972) with the marker allele as a covariate. The test statistic for linkage is identical to the traditional Sib-TDT. Monte-Carlo simulations are performed under different disease models to assess the increase in power of the age-adjusted Sib-TDT compared to the traditional Sib-TDT. We extend our method to multiallelic markers. An application using data on Alzheimer's Disease is also presented.

Power loss for linkage analysis due to the dichotomization of trichotomous phenotypes.

OBJECTIVES: Some traits, while naturally polychotomous, are routinely dichotomized for genetic analysis. Dichotomization, intuitively, leads to a loss of power to detect linkage, as some phenotypic variability is discarded. This paper examines this power loss in the context of a trichotomous trait. METHODS: To examine this power loss, we performed a simulation study where a trichotomous trait was simulated in a sample of 1,000 sib-pairs under various genetic models. The study was replicated 1,000 times. Linkage analysis using a variance components method, as implemented in Mx, was then performed on the trichotomous trait and compared with that on a dichotomized version of the trait. RESULTS: A comparison of the power and false positive rates of the analyses shows that power to detect linkage was increased by up to 22 percentage points simply by examining the trait as a trichotomy instead of a dichotomy. Under all models examined, the trichotomous analysis outperformed the dichotomous version. CONCLUSIONS: Comparable levels of false positive rates under both methods confirm that this power gain comes solely from the information lost upon dichotomization. Thus, dichotomizing tri- or poly-chotomous traits can lead to crippling power loss, especially in the case of many loci of small effect.

Familiality of symptom dimensions in depression.

BACKGROUND: Depression is a clinically heterogeneous disorder thought to result from multiple genes interacting with environmental and developmental components. A dimensional rather than a categorical approach to depressive phenotype definition may be more useful for identification of susceptibility genes. OBJECTIVES: To perform an exploratory factor analysis on a range of depressive and anxiety symptoms in a large, well-defined sample of depressed siblings, as well as a confirmatory factor analysis in a separate large group of unrelated depressed subjects, and to analyze correlations of identified symptom dimensions between depressed siblings. DESIGN: Subjects (N = 1034), including 475 sibling pairs, with a history of at least 2 depressive episodes were recruited from the Depression Network Study, a large-scale multicenter collection of families affected by recurrent unipolar depression. Subjects were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to the DSM-IV and the International Classification of Diseases, 10th Revision, using a computerized scoring program (CATEGO5). Factor analysis was carried out on 26 depression symptom items, including 4 anxiety screening items. Confirmatory factor analysis was performed on an independent sample of 485 depressed individuals. RESULTS: Four interpretable factors were identified: (1) mood symptoms and psychomotor retardation; (2) anxiety; (3) psychomotor agitation, guilt, and suicidality; and (4) appetite gain and hypersomnia. For each symptom group, a quantitative scale was constructed, and correlations between siblings were calculated. There was a moderate degree of sibling homotypia for some depressive symptoms, and factors 1, 2, and 3 showed significant positive familial correlation (0.145 [P =.001], 0.335 [P<.001], and 0.362 [P<.001], respectively). CONCLUSIONS: This is the first study of large, well-defined samples of depressed subjects in whom symptom dimensions have been derived and then confirmed using independent material. The significant correlations between siblings for 3 of the dimensions suggest substantial familial, perhaps genetic, etiologies.

The search for genetic risk factors associated with suicidal behavior.

BACKGROUND: Suicide and suicidal behavior are prevalent among individuals with psychiatric disorders, including alcohol dependence. A genome screen was performed in multiplex alcohol dependent families ascertained as part of the Collaborative Study on the Genetics of Alcoholism to identify chromosomal regions of interest related to two types of suicidal behavior: suicide attempts and suicidality. METHODS: Sibling pair analyses were used to conduct linkage analyses using both qualitative and quantitative suicide-related phenotypes. The qualitative trait of "suicide attempts" was examined using 59 affected sibling pairs. The quantitative trait of "suicidality" was examined using all possible 1366 sibling pairs and 705 independent sibling pairs. RESULTS: For the qualitative phenotype suicide attempts, chromosome 2 yielded a maximum lod score of 4.2. For the quantitative suicidality index, a maximum lod score of 1.8 was observed on chromosome 3, and a lod score of 1.5 was found on chromosome 1. CONCLUSIONS: This study represents the first genome-wide scan of suicidal behavior. Significant evidence of linkage was found on chromosome 2 for the phenotype suicide attempts, the same chromosomal region previously reported to be linked to alcohol dependence in this sample. This finding does not seem to be due solely to an association between suicide and alcohol dependence. There was more modest evidence of linkage to chromosomes 1 and 3 for suicidality; however, these findings did not reach statistical significance. There was no overlap in findings for these two phenotypes of suicidal behavior.

Psychosocial variables in children and teens of extended families identified through bipolar affective disorder probands.

OBJECTIVES: This multi-site study investigated the frequency of risk-related variables for developing an affective disorder using a within-pedigree control group. We wished to determine the effect of life events, social relationships, self-perceived competence, and aspects of home environment for youngsters from extended families with loading for bipolar disorder. Using a within-family contrast group, we address the following two issues: (1) Do offspring or their parents from families who do and do not have an affected parent report differences (i) in home environment? (ii) in frequency and type of offspring life events? and (iii) in social relations and self-perception? and (2) Do children or their parents who do or do not have an affective disorder report differently on these areas? METHODS: Juvenile offspring (n = 50) and their parents from 14 bipolar pedigrees were assessed. Structured interviews and self- or parent-reported instruments were used to compare offspring with an affected first-degree relative to those without and to compare offspring with or without an affective disorder. RESULTS: Only one significant psychosocial difference was found between offspring with or without a parent with an affective disorder but several were found between offspring who themselves did or did not have an affective disorder. These differences are in the areas of the need for discipline, social support, and dependent negative life events. CONCLUSIONS: The findings identify potential early psychosocial markers for affective disorder in high risk offspring.

Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.

Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P=.000000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.

Resting EEG in offspring of male alcoholics: beta frequencies.

This study examines the differences in beta (12-28 Hz) band power in offspring of male alcoholics from densely affected alcoholic families. We have attempted to investigate if the increase in beta power is a 'state' or 'trait' marker for alcoholism. This study also explores the gender differences in the expression of this potential risk marker. Absolute beta power in three bands-beta 1(12-16 Hz), beta 2 (16-20 Hz), and beta 3 (20-28 Hz)-in the eyes closed EEG of 171 high risk (HR) subjects who were offspring of male alcoholics and 204 low risk (LR) subjects with no family history of alcoholism, were compared for each gender separately using a repeated measures analysis of variance design. Alcoholic and non-alcoholic subjects within the high risk group were compared using a repeated measures design as a follow-up analysis. The present study demonstrated increased beta power in the resting EEG of offspring of male alcoholics. Male HR subjects had higher beta 1 (12-16 Hz) power and female HR subjects had increased power in beta 2 (16-20 Hz) and beta 3 (20-28 Hz) as compared with low risk participants. Female HR subjects also showed significantly increased beta 2 and beta 3 power if they had two or more alcoholic first-degree relatives when compared with HR females having only an affected father. Risk characteristics are expressed differentially in males and females and may be an index of differential vulnerability to alcoholism. The results indicate that increased EEG beta power can be considered as a likely marker of risk for developing alcoholism and may be used as a predictive endophenotype.

A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence.

Smoking is a highly heritable, addictive disorder that commonly co-occurs with alcohol dependence. The purpose of this study is to perform a genomic screen for habitual smoking and comorbid habitual smoking and alcohol dependence in families from the Collaborative Study on the Genetics of Alcoholism (COGA). Subjects were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) to evaluate alcohol dependence and habitual smoking (smoking one pack per day or more for at least 6 months). Sixty seven multi-generational families with 154 independent sibling pairs affected with habitual smoking were genotyped in a screening sample. Analyses on 79 multi-generational families with 173 independent sibling pairs were repeated in a replication sample. Sibpair analyses were performed using ASPEX. Four chromosomal regions in the screening sample had increased allele sharing among sibling pairs for habitual smoking with a LOD score greater than 1 (chromosomes 5, 9, 11, and 21). The highest LOD score was on chromosome 9 (LOD = 2.02; allele sharing 58.9%). Four chromosomal regions also had modest evidence for linkage to the comorbid phenotype habitual smoking and alcohol dependence (chromosomes 1, 2, 11, 15); and the strongest finding was on chromosome 2 (LOD = 3.30; allele sharing 69.1%). Previously identified areas (chromosomes 1 and 7) implicated in the development of alcohol dependence in this same data set did not provide evidence for linkage to habitual smoking in the screening sample. In the replication data set, there continued to be increased allele sharing near peaks identified in the screening sample on chromosomes 2 and 9, but the results were modest. An area on chromosome 7, approximately 60 cM from a location previously identified in linkage analysis with alcohol dependence, had increased allele sharing for the comorbid habitual smoking and alcohol dependence. These data provide evidence of specific genetic regions involved in the development of habitual smoking and not alcohol dependence. Conversely, genetic regions that influence the development of alcohol dependence do not appear to contribute to the development of habitual smoking. Finally, there is also evidence of an area on chromosome 2 that may reflect a common genetic vulnerability locus to both habitual smoking and alcohol dependence.

Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.

BACKGROUND: In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied. METHODS: Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions. RESULTS: One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p

Rapid switching of mood in families with multiple cases of bipolar disorder.

BACKGROUND: Heterogeneity within the diagnostic construct of bipolar disorder is most likely an obstacle to discovering its causes. Phenomena in the bipolar spectrum, including rapid cycling, cyclothymia, and affective instability of borderline personality, may be important markers of etiologic heterogeneity. Rapid switching of mood may be central to these phenomena. METHODS: We performed a case-control study, using diagnostic data from a multisite bipolar disorder linkage study, to explore clinical and demographic factors potentially related to rapid switching in bipolar disorder. Participants were 18 years or older and members of a family in which 2 or more first-degree relatives had bipolar disorder. Of 718 individuals interviewed and diagnosed as having bipolar disorder, 603 gave sufficient information about rapid switching and thus constituted the study group (60% female; mean age, 41 years; and mean education level, 13.8 years). RESULTS: Rapid switching of mood was reported by 44% of interviewees and was associated with early age at onset of bipolar disorder, higher risk of anxiety and substance abuse or dependence comorbidity, suicide attempts, antidepressant drug use, and having a relative with rapid switching. CONCLUSIONS: Rapid switching is associated with a complex clinical course of bipolar disorder. These results extend previous associations among rapid switching, anxiety, substance abuse, and early onset of bipolar disorder to a family study population. Rapid switching of mood seems to be the core phenomenon behind several variants of non-DSM-IV rapid cycling, DSM-III-R mixed states, and borderline personality disorder and the link connecting comorbidity, suicide, and early onset of bipolar disorder. Further biological investigation of the rapid-switching phenomenon is justified on epidemiologic grounds.