Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands

The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early-onset obsessive-compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between-marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER(+). The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples.     

Commingling and segregation analysis of reading performance in families of normal reading probands

This paper reports the results of commingling and genetic segregation analyses performed on a quantitative reading phenotype in 125 families ascertained through normal, nondisabled readers. Commingling analysis using SKUMIX suggested that the reading phenotype best fit a skewed, single distribution model. Complex segregation using POINTER was then performed on the power adjusted data. While there were some analytical ambiguities and complexities, the segregation analysis indicated that there was familial transmission of the phenotype and that a significant percentage of the variance in this phenotype could be attributed to a major gene with dominance. Because the estimated frequency of the putative dominant allele is 35, 57% of the population would carry at least one copy of this allele. This common allele, with low penetrance, accounted for 54% of the phenotypic variance in reading scores. These findings are considered in the context of our earlier report of major gene influence on a qualitative dyslexic phenotype in a sample of 133 dyslexic proband families that were originally matched to the present sample of control families (Penningtonet al., 1991). The applicability of a classic single gene, multifactorial-polygenic, and oligogenic or QTL models for reading ability/disability is discussed.     

A family study of obsessive-compulsive disorder with pediatric probands.

Obsessive-compulsive disorder (OCD) is a heterogeneous disorder of unknown etiology. We examined the lifetime history of obsessions, compulsions, and OCD in the first- and second-degree relatives of 35 pediatric probands with OCD and 17 controls with no psychiatric diagnosis. All available first-degree relatives were directly interviewed blind to proband status with two semi-structured interviews. Parents were also interviewed to systematically assess the family psychiatric history of first- and second-degree relatives. Best-estimate lifetime diagnoses were made using all available sources of information. Data were analyzed with logistic regression by the generalized estimating equation method and with robust Cox regression models. The lifetime prevalence of definite OCD was significantly higher in case than control first-degree relatives (22.5% vs. 2.6%, P < 0.05). Compared to controls, case first-degree relatives also had significantly higher lifetime rates of obsessions and compulsions (both P < 0.05). There was no significant difference between case and control second-degree relatives in lifetime rates of OCD. First-degree relatives of case probands with ordering compulsions had a significantly higher lifetime rate of definite and subthreshold OCD than relatives of case probands without ordering compulsions (45.4% vs. 18.8%, P < 0.05). The lifetime prevalence of definite OCD was significantly higher in case first-degree relatives with a history of tics than in case first-degree relatives without a tic history (57.1% vs. 20.9%, P < 0.01). The results provide further evidence that early-onset OCD is highly familial and suggest that two clinical variables are associated with its familial aggregation.     

Harm avoidance in subjects with obsessive-compulsive disorder and their families

INTRODUCTION: This study investigates the role of harm avoidance (HA) as a possible risk factor in the familiality of obsessive-compulsive disorder (OCD). HA is considered to be a genetically influenced personality trait with an increasingly understood neuroanatomical basis. METHOD: 75 subjects with OCD from hospital sites and a community sample and their 152 first degree relatives and 75 age and sex matched controls with their 143 first degree relatives were evaluated with structured clinical interviews (DSM-IV). HA was assessed with Cloninger's Tridimensional Personality Questionnaire (TPQ). RESULTS: Subjects with OCD had higher scores of HA than controls (p相似文献   

Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypoventilation syndrome

Idiopathic congenital central hypoventilation syndrome (CCHS) is a very rare syndrome with major respiratory complications. Hypothesizing that CCHS is the most severe manifestation of general autonomic nervous system dysfunction (ANSD), we applied a case-control family study design to investigate the genetics of ANSD. Fifty-two probands with CCHS were identified, as well as 52 age-, race-, and gender-matched controls. ANSD phenotypic features were characterized in the cases, controls, and their family members. Our earlier studies found that most ANSD symptoms were more likely in CCHS cases and their relatives than in controls and their relatives (P < 0.05). The goal of the current study was to determine if the familiality of ANSD was consistent with a genetic pattern. We performed major locus segregation analysis of ANSD utilizing regressive models. CCHS probands were assumed to be affected; controls and relatives were designated as affected if they had two or more relevant symptoms. The hypothesis of "no transmission and no familial effects" was rejected in both case and control families. Case families were consistent with transmission of a major effect; control families were not (the difference in the pattern of results was significant, P < 0.0001). In the total data set, the best-fitting model was codominant Mendelian inheritance of a major gene for ANSD. These case-control family studies support our hypothesis that CCHS is the most severe manifestation of a general ANSD, with a family pattern consistent with Mendelian transmission, and demonstrate the potential utility of the approach to studies of other, similarly intractable disorders.     

Parent-of-origin effect in the segregation analysis of bipolar affective disorder families

OBJECTIVE: The purpose of this study is to test for heterogeneity in bipolar families based on the differential parental transmission of disease. METHODS: Complex segregation analyses of 260 bipolar families, ascertained by the Johns Hopkins Bipolar Disorder Study, was performed based on the evidence for a parent-of-origin effect in the inheritance pattern by using REGD in Statistical Analysis for Genetic Epidemiology, Release 3.1 program. RESULTS: A Mendelian dominant model provided the best explanation in 57 paternal pedigrees (pedigrees with an affected paternal lineage). No evidence of Mendelian inheritance existed among 141 pedigrees showing maternal transmission. A likelihood ratio test for heterogeneity on the basis of best-fitting Mendelian dominant model showed significant differences between these two groups. CONCLUSION: These results suggest that pedigrees with no evidence of maternal transmission of bipolar disorder may represent a unique genetic subgroup of multiplex bipolar families.     

Complex segregation analysis for obsessive compulsive disorder and related disorders

Complex segregation analysis was applied to a sample of 107 Italian families with probands with obsessive compulsive disorder (OCD), using regressive logistic models to test for possible models of genetic transmission. We used two different phenotypic definitions of affection: 1) OCD; and 2) OCD plus Tourette's syndrome/chronic motor tics (CMT). Because of the potential relationship between OCD, Tourette's syndrome (TS), and other tic disorders, we considered these diagnoses to be determined by the same liability in subsequent steps of the analysis. For the 107 OCD families, the best fit was a dominant model of transmission (with a higher penetrance for females). When the phenotype boundaries were widened (OCD + CMT + TS), an unrestricted model of transmission became the best fit. We concluded that additional data are needed to support the hypothesis that Tourette's syndrome and OCD share a common etiology: on the basis of clinical and epidemiological considerations, the OCD phenotype probably presents a higher level of heterogeneity than the TS phenotype, and it could be regulated through different etiologic pathways.     

Familial aggregation of schizophrenia-spectrum disorders and obsessive-compulsive associated disorders in schizophrenia probands with and without OCD.

A substantial proportion of schizophrenia patients also has obsessive-compulsive disorder (OCD). To further validate the clinical validity of a schizo-obsessive diagnostic entity, we assessed morbid risks for schizophrenia-spectrum disorders and OC-associated disorders in first-degree relatives of schizophrenia probands with and without OCD. Two groups of schizophrenia probands [with OCD (n = 57) and without OCD (n = 60)] and community-based controls (n = 50) were recruited. One hundred eighty two first-degree relatives of probands with OCD-schizophrenia, 210 relatives of non-OCD schizophrenia probands, and 165 relatives of community subjects were interviewed directly [59.3% (108/182), 51.9% (109/210), and 54.5% (90/165), respectively], using the Structured Clinical Interview for Axis-I DSM-IV Disorders and Axis II DSM-III-R Personality Disorders and the remaining relatives were interviewed indirectly, using the Family History Research Diagnostic Criteria. Relatives of OCD-schizophrenia probands had significantly higher morbid risks for OCD-schizophrenia (2.2% vs. 0%; P = 0.033) and OCPD (7.14% vs. 1.90%; P = 0.014), and a trend towards higher morbid risk for OCD (4.41% vs. 1.43%; P = 0.08) compared to relatives of non-OCD schizophrenia probands. When morbid risks for OCD, OCPD, and OCD-schizophrenia were pooled together, the significant between-group difference became robust (13.74% vs. 3.33%; P = 0.0002). In contrast, relatives of the two schizophrenia groups did not differ significantly in morbid risks for schizophrenia-spectrum disorders, mood disorders, or substance abuse disorders. A differential aggregation of OC-associated disorders in relatives of OCD-schizophrenia versus non-OCD schizophrenia probands, provides further support for the validity of a putative OCD-schizophrenia ("schizo-obsessive") diagnostic entity.     

Complex segregation analysis of antibodies to thyroid peroxidase in old order amish families

Autoimmune thyroid disease (AITD) may be characterized by the measurement in serum of antibodies to thyroid peroxidase. A population of Old Order Amish individuals and families was investigated to determine the prevalence of these antibodies and to examine hypotheses about the mode of transmission of thyroid antibodies. Complex segregation analysis were performed on 4 large multi-generational Old Order Amish families composed of 26 nuclear families containing 199 first degree relatives. Several alternative hypotheses of genetic transmission were examined. Hypotheses of no transmission, polygenic inheritance, single locus transmission, and mixed inharitance were compared. The analyses incorporated population prevalences obtained from a random sample of of individuals. Result suggest that the pattern of transmission of thyroid antibodies in these families is consistent with a mixed model in which the major gene is transmitted in an autosomal dominant pattern. The mixed model postulates that there is a single gene of major effect as well as a polygenic component that can act separately and/or together to confer susceptibility for this phenotype. The parameter estimates for the major locus are: gene frequency (q), 0.16 ± 0.01; maximum male penetrance, 0.35; and maximum female penetrance, 0.70. The heritability of the polygenic background is estimated at 0.41. © 1993 Wiley-Liss, Inc.     

Genome‐wide linkage analysis of families with obsessive‐compulsive disorder ascertained through pediatric probands

The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early‐onset obsessive‐compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between‐marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER⁺. The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples. © 2002 Wiley‐Liss, Inc.     

Heritability and clinical features of multigenerational families with obsessive-compulsive disorder and hoarding.

To date, only one complete genome screen for obsessive-compulsive disorder (OCD) has been published. That study identified a region of suggestive linkage (maximum lod score of 2.25) with a relatively small sample size (N = 56; 27 with OCD). Additional complete genome screens are needed to confirm this finding and identify other regions of linkage. We present the clinical characteristics and power to detect linkage of 11 multigenerational families with OCD and hoarding (N = 92; 44 with OCD), as well as heritability estimates for several quantitative traits. Families with at least two individuals with OCD were identified through probands with childhood-onset OCD. Expected lod scores were calculated for simulated genetic marker data under an additive and two dominant models assuming a dense SNP marker map. All affected individuals had an early age of onset (18 or younger). Hoarding was present in 46% of subjects. Obsessive-compulsive symptoms and hoarding were highly heritable. The maximum mean expected lod score was 3.31 for OCD and 1.39 for hoarding. We found reasonable power to detect regions of interest (lod = 2) for OCD in these families, but will need to expand our family collection to have adequate power to detect regions of interest for hoarding.     

Saccadic abnormalities in psychotropic-naive obsessive-compulsive disorder without co-morbidity

BACKGROUND: Oculomotor studies have found saccadic abnormalities in obsessive-compulsive disorder (OCD), lending support for models postulating a central role for inhibition in OCD. Saccadic abnormalities in OCD may also be potential candidates for a biological marker, important for more endophenotype-oriented research. Saccadic abnormalities have not been examined in psychotropic-naive patients with OCD without co-morbidity. METHOD: We compared the error rates and latencies of 14 carefully selected adult psychotropic-naive patients with OCD with no co-morbid diagnosis and 14 pairwise matched healthy controls on a fixation task, on a prosaccade task and on an antisaccade task. RESULTS: Patients with OCD showed normal error rates on all tasks, but latencies on the antisaccade task were significantly increased. CONCLUSIONS: Our results indicate that patients with OCD have no gross impairment of oculomotor inhibitory capacities, but may have a disturbed capacity to deliberately initiate a saccade to an imagined target.     

Binge antecedents in obese women with and without binge eating disorder

In this study, women with binge eating disorder (BED; n = 41) and weight- and age-matched comparison women without BED (NBED; n = 38) monitored their eating for 6 days, using handheld computers to measure mood, appetite, and setting at all eating episodes and comparison noneating episodes. Poor mood, low alertness, feelings of poor eating control, and craving sweets all preceded binge episodes for the BED group. An unanticipated finding was the frequent report of binge episodes in the comparison group; only feelings of poor eating control and craving sweets predicted binge episodes in this group. Binge eating NBED women tended to experience worse mood, less control, and more craving than other NBED women, contributing to evidence of the close relationship of binge eating and decrements in emotional and appetitive functioning.     

Thought disorder in patients with obsessive-compulsive disorder

We examined the presence of disordered thinking/perception in patients with obsessive-compulsive disorder (OCD). Recently, an obsession model has been proposed, which classifies obsessions into two different subtypes: autogenous obsessions and reactive obsessions (Lee & Kwon, 2003). Based on this model, we hypothesized that OCD patients primarily displaying autogenous obsessions as opposed to reactive obsessions would display more severely disordered thinking/perception. We compared 15 OCD patients primarily displaying autogenous obsessions (AOs), 14 OCD patients primarily displaying reactive obsessions (ROs), 32 patients with schizophrenia (SPRs), and 28 patients with other anxiety disorders (OADs) with respect to thought disorders as assessed by the Comprehensive System of the Rorschach Inkblot Test. Results indicated that both AOs and SPRs displayed more severe thought disorders compared to ROs or OADs. Theoretical and clinical implications are discussed.     

New segregation analysis of panic disorder

We performed simple segregation analyses of panic disorder using 126 families of probands with DSM-III-R panic disorder who were ascertained for a family study of anxiety disorders at an anxiety disorders research clinic. We present parameter estimates for dominant, recessive, and arbitrary single major locus models without sex effects, as well as for a nongenetic transmission model, and compare these models to each other and to models obtained by other investigators. We rejected the nongenetic transmission model when comparing it to the recessive model. Consistent with some previous reports, we find comparable support for dominant and recessive models, and in both cases estimate nonzero phenocopy rates. The effect of restricting the analysis to families of probands without any lifetime history of comorbid major depression (MDD) was also examined. No notable differences in parameter estimates were found in that subsample, although the power of that analysis was low. Consistency between the findings in our sample and in another independently collected sample suggests the possibility of pooling such samples in the future in order to achieve the necessary power for more complex analyses. © 1996 Wiley-Liss, Inc.     

强迫症患者脑灰质基于体素的形态学研究

目的 运用基于体素的形态学测量(VBM)分析方法研究强迫症患者大脑灰质体积的改变,以及强迫症患者大脑灰质体积和耶鲁布朗强迫量表(Y-BOCS)评分的相关性.方法 收集20例未服药强迫症患者和20例健康对照组,对被试的大脑结构进行磁共振扫描.采用VBM分析方法对所获得的数据进行统计分析.结果 ①强迫症患者组较对照组在3个...     

Gender in obsessive-compulsive disorder and obsessive-compulsive spectrum disorders

Summary Background: There is increasing recognition that obsessive-compulsive disorder (OCD) and putative OCD spectrum disorders (OCSDs) are not homogenous entities. Gender may provide an important window onto the heterogeneity of these various disorders. Methods: A MEDLINE review of gender issues in OCD and putative OCD spectrum disorders (excluding eating disorders) was undertaken (1965–2000). These included demographic variables, clinical phenomenology, etiological factors, and treatment implications. Results: OCD differs from other anxiety disorders in having an approximately equal male:female gender ratio. OCSDs (e.g. body dysmorphic disorder) may have an equal gender ratio, may be more common in women (e.g. trichotillomania, hypochondriasis) or may be more common in men (e.g. Tourette's disorder). Etiological factors may differ across gender; an association between perinatal or early brain injury and OCD or Tourette's appears particularly important in males, while OCD and trichotillomania may also begin during pregnancy or shortly after childbirth with exacerbation of symptoms during menstruation. It is not clear that anti-androgens are effective in OCD, nor that gender predicts response to serotonin reuptake inhibitors in this disorder. Conclusion: There is a relative scarcity of literature addressing gender issues in OCD and putative OCSDs. That literature which does exist is not entirely conclusive, but raises a number of interesting questions for future research.     

Enhanced APOE2 transmission rates in families with autistic probands

We have previously described linkage/association between reelin gene polymorphisms and autistic disorder. APOE also participates in the Reelin signaling pathway, by competitively antagonizing Reelin binding to APOE receptor 2 and to very-low-density lipoprotein receptors. The APOE2 protein variant displays the lowest receptor binding affinity compared with APOE3 and APOE4. In this study, we assess linkage/association between primary autism and APOE alleles in 223 complete trios, from 119 simplex Italian families and 44 simplex and 29 multiplex Caucasian-American families. Statistically significant disequilibrium favors the transmission of epsilon2 alleles to autistic offspring, over epsilon3 and epsilon4 (allele-wise transmission/disequilibrium test [TDT], chi2 = 6.16, 2 degrees of freedom [d.f.], P<0.05; genotype-wise TDT, chi2 = 10.68, 3 d.f., P<0.05). A novel epsilon3r allele was also discovered in an autistic child and his mother. Autistic patients do not differ significantly from unaffected siblings (allele-wise TDT comparing autistic patients versus unaffected sibs, chi2 = 1.83, 2 d.f., P<0.40, not significant). The major limitation of this study consists of our small sample size of trios including one unaffected sibling, currently not possessing the statistical power necessary to conclusively discriminate a specific association of epsilon2 with autism, from a distorted segregation pattern characterized by enhanced epsilon2 transmission rates both to affected and unaffected offspring. Our findings are thus compatible with either (a) pathogenetic contributions by epsilon2 alleles to autism spectrum vulnerability, requiring additional environmental and/or genetic factors to yield an autistic syndrome, and/or (b) a protective effect of epsilon2 alleles against the enhanced risk of miscarriage and infertility previously described among parents of autistic children.