Affective disorder not linked to HLA

These analyses focused on the relationship of affective disorders to HLA. The sample of 86 previously unpublished families from Ontario and 10 unpublished pedigrees from Newfoundland, as well as the original Weitkamp et al. [1981] sample of 20 families, the samples provided by NIMH [Goldin et al., 1982] (18 families), and Egeland et al. [1987] (2 large pedigrees), were examined using sib pair methods as well as standard linkage analysis of the full pedigrees. A variety of genetic models were examined. There was no evidence for linkage from any of the samples based on either analytic approach or for any genetic model. Groups of sibling pairs concordant for affective illness, concordant for being well, or discordant for affective illness did not differ in the proportion of genes identical by descent. No group differed significantly from 50%. From the analysis of full pedigrees, linkage to HLA could be excluded to a distance of approximately 20 to 25 centimorgans. There was no evidence for linkage heterogeneity. These results argue against linkage of affective disorder to HLA.     

Genetic analysis of IDDM: summary of GAW5 IDDM results

This paper summarizes the analyses by participants in the insulin-dependent diabetes mellitus (IDDM) component of Genetic Analysis Workshop 5 (GAW5). The data were obtained from 94 families with two or more IDDM sibs. Topics treated in the Workshop analysis included the following: methods for detecting associations and linkage, the contribution by HLA-linked and -unlinked loci to IDDM susceptibility, the role of subtypes of the serologically defined HLA specificities, the implications of associated diseases other than IDDM in the families, the significance of antibodies to Coxsackie viruses, and of autoantibodies to pancreatic islet cells and insulin, and the use of genetic models to analyze the inheritance of IDDM. There was agreement that an explanation for the data on multiplex IDDM families must include the following features: 1) There is a susceptibility locus (or loci) in the HLA region. 2) The HLA-linked factor(s) are more complex than a single locus with one disease and one nondisease allele. 3) There is additional familial correlation beyond that explained by HLA-linked susceptibility, which may be genetic and/or environmental. With regard to the third feature, IDDM-GAW5 included data on variation in Gm haplotypes and at the insulin gene, two regions unlinked to HLA. However, there was no direct evidence (i.e., from marker segregation) that the additional factor, if genetic, is linked to either Gm or the insulin gene. Nevertheless, a significant difference was found between "diabetic" and "control" insulin genes with respect to frequency of class 1 alleles for the 5' flanking polymorphism, strongly suggesting linkage.     

Multiprofessional care and mental health in pregnant women

OBJECTIVE: To identify non-psychotic affective disorders in pregnant women, to intervene by means of psychoprophylactic groups, and to evaluate possible alterations following intervention. METHODS: One-hundred and three pregnant women (71 adults and 32 adolescents) were seen at a community program in the Paraisópolis neighborhood in the city of Sao Paulo, southeastern Brazil. We used the following instruments: Self Reporting Questionnaire and Beck Depression Inventory. Ten weekly two-hour meetings were held, addressing the link between mother and fetus and subjects related to mother and child, and answering mother's doubts. We used the chi-squared test (chi2) to compare mental health before and after the intervention, with a significance level of p<0.05. RESULTS: Affective disorders were found in 45 pregnant women (43.7%) before the intervention and in 23 (22.3%) after the intervention. The impact of the intervention on affective disorders was statistically significant (p=0.001). Twenty-one women (20.4%) showed depression before the intervention, and 13 (12.6%) after the intervention, a non-significant difference (p=0.133). CONCLUSIONS: Multiprofessional care can prevent, detect, and treat affective disorders during pregnancy in both adults and adolescents.     

Test of Association for Quantitative Traits in General Pedigrees: The Quantitative Pedigree Disequilibrium Test

Many statistical methods have been proposed in recent years to test for genetic linkage and association between genetic markers and traits of interest through unrelated nuclear families. However, most of these methods are not valid tests of association in the presence of linkage when some of the nuclear families are related. As a result, related nuclear families in large pedigrees cannot be included in a single analysis to test for linkage disequilibrium. Recently, Martin et al. [Am J Hum Genet 67:146–54, 2000] proposed the pedigree disequilibrium test (PDT) to test for linkage and association in general pedigrees for qualitative traits. In this article, we develop a similar quantitative pedigree disequilibrium test (QPDT) to test for linkage and association in general pedigrees for quantitative traits. We apply both the PDT and the QPDT to analyze the sequence data from the seven candidate genes in the simulated data sets in the Genetic Analysis Workshop 12. © 2001 Wiley‐Liss, Inc.     

Genetics of IDDM: evidence for complex inheritance with HLA

Analysis of the Fifth Genetic Analysis Workshop (GAW5) insulin-dependent diabetes mellitus (IDDM) data leads to the following conclusions: 1) With a maximum-likelihood affected sib pair method, there is strong evidence for linkage with HLA and no evidence for linkage with INS, Gm, or Km. 2) Susceptibility as defined by HLA genotypes is very complex. Each DR allele has a unique susceptibility, and DR3 and DR4 haplotype associations for DR 3/4 genotypes are different from those for 3/X and 4/X. 3) Risk is substantially higher in sibships with an affected father compared to those with an affected mother. This excess cannot be attributed to transmission distortion at HLA.     

Adolescents with bulimia nervosa and eating disorder not otherwise specified-purging only

OBJECTIVE: The purpose of the study was to better understand the phenomenology of bulimic symptomatology in an adolescent clinic sample. METHOD: Adolescents with bulimia nervosa (BN; n = 36) and eating disorders not otherwise specified-purging but no objective bulimic episodes (EDNOS-P; n = 20) were compared on the Eating Disorder Examination (EDE), the Beck Depression Inventory (BDI), the Rosenberg Self-Esteem Scale (RSES), and the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). RESULTS: Subjects with EDNOS-P and BN were equivalent in terms of age and weight, but were less likely to have intact families. Nearly one half of EDNOS-P subjects purged exclusively outside of eating episodes in which they experienced a sense of loss of control. Although still at clinically significant levels, EDNOS-P subjects reported less concerns regarding weight, shape, and eating relative to BN. Groups were not significantly different on psychiatric comorbidity, but differed on self-esteem. DISCUSSION: Results prompt reappraisal of current criteria of BN to encompass those who purge without binge eating.     

HLA may be involved in resistance and susceptibility to affective disorders

The role of HLA in susceptibility to affective disorders was assessed by sib pair linkage analysis and by association studies. Unipolar Disorder (UD) and Bipolar Disorder (BD) were studied separately. Both the sib pair data and the antigen frequency distribution suggested an HLA-linked susceptibility to UD. For BD however, the HLA haplotype sharing distribution in sib pairs was random, but the antigen frequencies suggested at least one positive association and one negative association with HLA. The lack of evidence for linkage to HLA from sib pairs may have been due to the genetic heterogeneity of BD.     

Single Region Linkage Analyses of Asthma: Description of Data Sets

Linkage (genotypic) data from the 5q31–33 candidate region for asthma were contributed to Genetic Analysis Workshop 12 by members of the International Consortium on Asthma Genetics (COAG). Data came from five independent studies sampled from five countries. Genotypic data for a total of 26 markers were available, although the number of markers typed in each data set varied. Phenotypic and genotypic data was available from a total of 569 families and 3,175 subjects. The phenotypic data available varied among the studies; however information regarding physician‐diagnosed asthma and total serum IgE levels was available in all five studies. This paper describes the ascertainment, data collection methods, phenotypic data, and genotypic data available for the single linkage region analyses undertaken for Genetic Analysis Workshop 12. © 2001 Wiley‐Liss, Inc.     

Alcoholism and related traits: a summary of Group 13 contributions

Ten groups set out to study the genetics of alcoholism, using various measures of alcohol dependence such as Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, and related endophenotypes such as the electrophysiological evaluation of event-related potentials. The groups used both genome-wide microsatellite and single-nucleotide polymorphism (SNP) genotyping data in families selected from the Collaborative Study on the Genetics of Alcoholism. The majority of investigators studied alcohol-related phenotypes and chose linkage rather than association analysis. The analysis of SNP data presented several challenges, including marker linkage disequilibrium issues and computational limitations. Many groups pursued novel techniques, both in dealing with the SNP data and the definition of phenotypes. While there was a limited amount of concordance among linkage findings, it was very instructive to see so many new strategies at work. Generally the SNP genotype data seemed to yield more information for multipoint linkage analysis than the microsatellite data, a finding that will benefit the genetic analysis of complex disease in the future. A novel linkage peak was detected using the SNP markers.     

Physician diagnosed mental ill-health in male and female workers

Background Although there have been many studies of work demands and self-reported job strain, few have examined incident physician-diagnosed mental ill-health (MIH) by detailed occupational group. Aims To investigate whether linkage of occupation from worker compensation claims to diagnoses from administrative health records can give credible information on occupation and incidence of MIH by diagnostic group and gender. Methods Information on occupation from all worker compensation claims 1995-2004 in Alberta, Canada were linked to administrative health records of MIH diagnoses. Relative risks for affective, substance use and psychotic disorders by four digit occupational codes were calculated for men and women aged 18-65 years in a log-binomial regression adjusting for age and stratifying by sex. Results There were 327883 male and 88483 female compensation claims available for the analysis of incident cases. Affective disorders (5.2% men, 11.5% women) were much more common than substance use disorders or psychotic disorders (both ≤1%) in this population of working people. In men, the type of work appeared to either protect from or precipitate affective disorders, but no protective effect was seen for women. Substance use disorders clustered mainly in physically demanding occupations typically involving employment outside the urban areas. New onset psychotic disease was rare but seen in excess in painters, boilermakers and chefs. Conclusions Data linkage of occupation close to the time of new onset MIH can provide important insight into the relation between work and physician-diagnosed MIH and indicate areas in which intervention might be appropriate.     

Description of the National Institute of Mental Health family study of affective disorders

The NIMH family study consisted of 172 probands with affective disorder and 43 normal control probands. Psychiatric disorders were diagnosed in relatives over the age of 18 using Research Diagnostic Criteria based on personal interviews, medical records, and family history information. Some families were also genotyped for red cell, serum, and HLA marker loci. Previous analyses of these data have shown that affective disorders aggregate in families. Segregation analyses have not been able to define the mode of inheritance.     

Assessment and implications of linkage disequilibrium in genome-wide single-nucleotide polymorphism and microsatellite panels

Linkage disequilibrium (LD) between markers is more likely to exist in dense genome-wide single-nucleotide polymorphism (SNP) panels than in microsatellite panels. As part of Genetic Analysis Workshop 14 (GAW14), the extent of LD in the Illumina linkage panel III and the Affymetrix Genechip 10 K mapping array was assessed, using data from the Collaborative Study on the Genetics of Alcoholism (COGA). The impact of LD on linkage results was examined in COGA and simulated data, and characteristics of SNPs were assessed for their ability to detect population substructure and predict haplotypes. The authors of the papers summarized here observed greater LD in the Affymetrix than in the Illumina panel, possibly due to increased marker density in the Affymetrix panel, and found greater LD on chromosome X than on the autosomes. Simulation analyses suggest that intermarker LD can cause an upward bias in linkage statistics; however, the impact of LD on linkage analysis depends on the proportion of ungenotyped founders and the extent of LD. No large effect of LD on linkage peaks was observed in COGA analyses. In addition, the papers summarized here found that SNPs with high minor allele frequencies were the most informative compared with microsatellites for the detection of population substructure, and that SNPs in higher LD, and small numbers of SNPs, were the most reliable for haplotype prediction. As ease of genotyping continues to increase, study design and SNP selection for linkage and association studies (including genome-wide association studies) will be improved with consideration of LD in the particular populations studied.     

Effect of linkage disequilibrium between markers in linkage and association analyses

Contributions to Group 17 of the Genetic Analysis Workshop 15 considered dense markers in linkage disequilibrium (LD) in the context of either linkage or association analysis. Three contributions reported on methods for modeling LD or selecting a subset of markers in linkage equilibrium to perform linkage analysis. When all markers were used without modeling LD, inflated evidence for linkage was observed when parental genotypes were missing. All methods for handling LD led to some decreased linkage evidence. Two groups performed a genome-wide association scan using either mixed models to account for known or unknown relatedness between individuals, trend tests or combination statistics. All methods failed to detect four of the eight simulated loci because of low LD in some regions. Three groups performed association analysis using simulated dense markers on chromosome 6, where a simulated HLA-DRB1 locus played a major role in disease susceptibility along with two additional loci of smaller effect. The overall conditional genotype method correctly identified both additional loci while a novel transmission disequilibrium test-statistic to combine studies with non-overlapping markers identified one HLA locus after stratifying on the parental HLA-DRB1 genotypes; LD mapping using the Malécot model mapped two loci in this region, even when using greatly reduced marker density. While LD between markers appears to be a nuisance that may cause spurious linkage results with missing parental genotypes in linkage analysis, association analysis thrives on LD, and disease genes fail to be detected in regions of low LD.     

Toronto-Rochester Depression study of 116 HLA-typed kindreds

The Toronto-Rochester Depression study consisted of 116 pedigrees ascertained for multiple cases of major affective disorders. Among the 857 psychiatrically evaluated family members, of whom more than 85% were given a structured interview, 363 had major affective disorder by Research Diagnostic Criteria and 385 had no history of psychological aberration. HLA region genes were typed in 804 of these persons.     

Affective disorders: evaluation of a three-allele model accounting for clinical heterogeneity

The group of major affective disorders is clinically heterogeneous. In the genetic linkage study of the Old Order Amish [Egeland et al., 1987] the same disease gene appears to be responsible for the occurrence in one family of several clinically variant forms of affective disorders. Apparently other genetic or environmental factors determine the clinical presentation of this disease gene. We evaluated a three-allele model where the clinical expression of the disease allele is determined by the other allele at the same locus. In the presence of a proposed modifying allele the disease allele is expressed as major depression, in the presence of the normal (neutral) allele as bipolar disorder (I or II). We applied this model in our analysis of the Old Order Amish data. In analysis of linkage between the locus for affective disorders and two DNA markers on chromosome 11p, we obtained considerably higher likelihood values under the three-allele model than under a comparable two-allele model. Also, lodscores were higher under the three-allele model, with differences in lodscores between both models ranging from 0.95 to 1.34.     

Comparison of single-nucleotide polymorphisms and microsatellite markers for linkage analysis in the COGA and simulated data sets for Genetic Analysis Workshop 14: Presentation Groups 1, 2, and 3

The papers in presentation groups 1-3 of Genetic Analysis Workshop 14 (GAW14) compared microsatellite (MS) markers and single-nucleotide polymorphism (SNP) markers for a variety of factors, using multiple methods in both data sets provided to GAW participants. Group 1 focused on data provided from the Collaborative Study on the Genetics of Alcoholism (COGA). Group 2 focused on data simulated for the workshop. Group 3 contained analyses of both data sets. Issues examined included: information content, signal strength, localization of the signal, use of haplotype blocks, population structure, power, type I error, control of type I error, the effect of linkage disequilibrium, and computational challenges. There were several broad resulting observations. 1) Information content was higher for dense SNP marker panels than for MS panels, and dense SNP markers sets appeared to provide slightly higher linkage scores and slightly higher power to detect linkage than MS markers. 2) Dense SNP panels also gave higher type I errors, suggesting that increased test thresholds may be needed to maintain the correct error rate. 3) Dense SNP panels provided better trait localization, but only in the COGA data, in which the MS markers were relatively loosely spaced. 4) The strength of linkage signals did not vary with the density of SNP panels, once the marker density was approximately 1 SNP/cM. 5) Analyses with SNPs were computationally challenging, and identified areas where improvements in analysis tools will be necessary to make analysis practical for widespread use.     

Substance abuse disorders in the parents of ADHD children, and parents of normal children

The objective of the study was to compare the attention-deficit/ hyperactivity, and substance abuse disorders background in the parents of children with attention-deficit/ hyperactivity disorder (ADHD), and the parents of normal children. The available sampling method was used to choose 400 parents of children (200 parents of children with ADHD and 200 parents of normal children), the ages of children were 6-18 years old. The data were collected through the Schedule for Affective Disorders and Schizophrenia (SADS) for parents and the Kiddy Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL), Connors Adult ADHD Rating Scale (CAARS) and the Wender Utah Rating Scale (WURS) for adult ADHD. The results were analyzed by using SPSS-17 software, based on two-variable Chi-Square and t-tests.and P value in all disorders were equals to P<0.05. The results indicated that substance abuse in parents of children with ADHD is 21% more prevalent, and parents of children with ADHD compared to parents of normal children have 2% ADHD, 9% attention deficit disorder, and 1% hyperactivity disorder more in their background. Therefore, we conclude that there exists a significant difference between the above mentioned disorders in the parents of children with ADHD, and parents of normal children. The high prevalence rate of disorders and background of ADHD in families of individuals with ADHD shows the probability of effect of inheritance in the disorder. Also, it shows that parents of children with ADHD have more substance abuse and history of ADHD in their background.     

The Northern Ireland Early Onset Psychosis Study: Phenomenology and Co-morbidity in the First 25 Cases

Diagnosing psychotic disorders in young people is difficult. High rates of co-morbidity may be one reason for this difficulty, but it may also be the case that current diagnostic categories are not the most useful when approaching the care of young people with psychotic symptoms. The Northern Ireland Early Onset Psychosis Study is the first study to investigate psychotic disorders in children and adolescents in this region. Young people presenting with psychotic symptoms with onset before their 18th birthday were prospectively ascertained over a three-year period (2001-2004). Those who provided informed consent were subject to a diagnostic interview using the Kiddie-Schedule for Affective Disorders and Schizophrenia—Present and Lifetime Version. Twenty-five young people have completed the full assessment process to date. Ten young people met criteria for schizophrenia, 11 for affective psychosis, two for schizoaffective disorder and two for schizophreniform disorder. Twenty-one (80%) subjects also fulfilled criteria for at least one other DSM-IV diagnosis. In conclusion, whilst all subjects met criteria for one or other psychotic disorder, co-morbidity was common in this clinical sample. Greater awareness of the difficulties encountered when trying to reach a diagnosis in this age group may help to improve treatment outcomes.     

Specificity in the relationship between depressive and eating disorder symptoms in remitted and nonremitted women.

OBJECTIVE: There is a strong association between eating disorders and depression. However, because both eating disorder symptoms and depression are multifactorial, this study explored the relationship between these two disorders in women with eating disorders and women in remission. METHOD: Two hundred and eight (mostly female) volunteers with a history of eating disorders participated. They completed a self-report questionnaire of eating disorder symptoms, the Short Evaluation for Eating Disorders (SEED), and a questionnaire measuring depression, the Beck Depression Inventory (BDI). RESULTS: According to the SEED, 57 volunteers were classified as being in remission and 151 were classified as being ill. Those who were in remission were significantly less depressed overall than those who were still ill with 72% of the former falling in the "not depressed" or "mildly depressed" categories and 73% of the latter falling in the "moderately" or "severely depressed" categories. Factor analyses of the SEED and BDI identified three subscales of eating disorder symptoms (dietary restriction, bulimia, and body mass index [BMI]/menstruation) and two subscales of depression (cognitive and somatic/affective). Dietary restriction and bulimia, but not BMI/menstruation, were uniquely associated with the cognitive symptoms of depression. However, none of the eating disorder symptoms were uniquely associated with the somatic/affective symptoms of depression. DISCUSSION: Although eating disorders and depression share considerable comorbidity, a specific association is restricted to that between the cognitive and behavioral symptoms of eating disorders and the cognitive symptoms of depression.     

Genetic analysis of bipolar disorder: Summary of GAW10

Participants in the Bipolar Disorder component of Genetic Analysis Workshop 10 had access to five distributed data sets containing chromosome 18 marker data and five data sets containing chromosome 5 data. A total of 25 groups participated in analyses and applied a myriad of methodologically innovative approaches to these data. Contributors focused on how to: (1) best define the phenotype from the spectrum of affective diagnoses; (2) test for a parent-of-origin effect in the transmission of bipolar illness and assess whether sharing in affected sib pairs depends on the sex of the transmitting parent; (3) evaluate the effects of misspecification of marker allele frequencies; (4) examine the putative candidate loci provided; (5) investigate the mode of inheritance; and (6) perform a meta-analysis to combine multiple data sets in a single analysis. Taken as a whole, the results would appear suggestive, but not definitive for linkage to a bipolar susceptibility locus on chromosome 18. The evidence for linkage appeared to increase as the diagnostic definition of the phenotype was broadened. Multipoint analyses seem to provide less evidence. It is possible that, because adjacent markers may be present in different data sets, the multipoint methods are combining marker data from different studies in a more comprehensive way than single marker analyses. Evidence on chromosome 5 and evidence for candidate loci were minimal. A discussion of problems inherent in combined analyses is given. © 1997 Wiley-Liss, Inc.