Hoarding behavior occurs frequently in obsessive–compulsive disorder (OCD). Results from previous studies suggest that individuals with OCD who have hoarding symptoms are clinically different than ...non-hoarders and may represent a distinct clinical group. In the present study, we compared 235 hoarding to 389 non-hoarding participants, all of whom had OCD, collected in the course of the OCD Collaborative Genetics Study. We found that, compared to non-hoarding individuals, hoarders were more likely to have symmetry obsessions and repeating, counting, and ordering compulsions; poorer insight; more severe illness; difficulty initiating or completing tasks; and indecision. Hoarders had a greater prevalence of social phobia and generalized anxiety disorder. Hoarders also had a greater prevalence of obsessive–compulsive and dependent personality disorders. Five personality traits were independently associated with hoarding: miserliness, preoccupation with details, difficulty making decisions, odd behavior or appearance, and magical thinking. Hoarding and indecision were more prevalent in the relatives of hoarding than of non-hoarding probands. Hoarding in relatives was associated with indecision in probands, independently of proband hoarding status. The findings suggest that hoarding behavior may help differentiate a distinct clinical subgroup of people with OCD and may aggregate in some OCD families. Indecision may be a risk factor for hoarding in these families.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Despite progress in identifying homogeneous subphenotypes of obsessive-compulsive disorder (OCD) through factor analysis of the Yale Brown Obsessive-Compulsive Scale Symptom Checklist ...(YBOCS-SC), prior solutions have been limited by a reliance on presupposed symptom categories rather than discrete symptoms. Furthermore, there have been few attempts to evaluate the familiality of OCD symptom dimensions. The purpose of this study was to extend prior work by this collaborative group in category-based dimensions by conducting the first-ever exploratory dichotomous factor analysis using individual OCD symptoms, comparing these results to a refined category-level solution, and testing the familiality of derived factors. Participants were 485 adults in the six-site OCD Collaborative Genetics Study, diagnosed with lifetime OCD using semi-structured interviews. YBOCS-SC data were factor analyzed at both the individual item and symptom category levels. Factor score intraclass correlations were calculated using a subsample of 145 independent affected sib pairs. The item- and category-level factor analyses yielded nearly identical 5-factor solutions. While significant sib–sib associations were found for four of the five factors, Hoarding and Taboo Thoughts were the most robustly familial ( rICC ≥ 0.2). This report presents considerable converging evidence for a five-factor structural model of OCD symptoms, including separate factor analyses employing individual symptoms and symptom categories, as well as sibling concordance. The results support investigation of this multidimensional model in OCD genetic linkage studies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The ...authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.
X-linked cone dystrophy is a type of hereditary retinal degeneration characterized by a progressive dysfunction of the day vision or photopic (cone) system with preservation of night vision or ...scotopic (rod) function. The disease presents with a triad of photophobia, loss of color vision and reduced central vision. This phenotype is distinct from retinitis pigmentosa (RP) in which there are prominent night and peripheral vision disturbances. X-linked cone dystrophy is a genetically heterogeneous disorder, with linkage to loci on Xp11.4--Xp21.1 (COD1, OMIM 304020) and Xq27 (COD2, OMIM 303800). COD1 maps to a region that harbors the RPGR gene, mutations in which account for >70% of patients with X-linked RP. The majority of these mutations reside in one purine-rich exon, ORF15, encoding 567 amino acids with a repetitive domain rich in glutamic acid residues. We mapped two families with X-linked cone dystrophy to the COD1 locus and identified two distinct mutations in ORF15 in the RPGR gene (ORF15+1343_1344delGG and ORF15+694_708del15) leading to a frame-shift and premature termination of translation in one case and a deletion of five amino acids in another. Consistent with expression of RPGR in rods and cones, our results show that mutations in RPGR, in addition to X-linked RP, can also cause cone-specific degeneration.
Objective: Drugs take effect at different times in different individuals. Consequently, researchers seek to examine how the timing of the biological response to drugs may be affected by factors such ...as gender, genotypes, age, or baseline symptom scores. Methods: Typically, studies measure symptoms immediately after the initiation of drug treatment and then at a sequence of later time points. In this study, we develop a statistical mixture model for analyzing such longitudinal data. Our method estimates the onset of drug effect and assesses the association between the probability distribution of the onset times and possible contributing factors. Our mixture model treats the timing of onset as missing for each individual but restricts it, for simplicity, to two possible onset points, early or late. To estimate the model, we use an expectation-maximization-based approach and provide the general formulas of the variance and covariance matrix for the estimated parameters. Results: We evaluate the model's overall utility and performance via simulation studies. In addition, we illustrate its use by application to longitudinal data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The algorithm identified age and anxiety status as significant factors in affecting the onset distribution of citalopram (Celexa).
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
Both common and rare genetic variants have been shown to contribute to the etiology of complex diseases. Recent genome-wide association studies (GWAS) have successfully investigated how common ...variants contribute to the genetic factors associated with common human diseases. However, understanding the impact of rare variants, which are abundant in the human population (one in every 17 bases), remains challenging. A number of statistical tests have been developed to analyze collapsed rare variants identified by association tests. Here, we propose a haplotype-based approach. This work inspired by an existing statistical framework of the pedigree disequilibrium test (PDT), which uses genetic data to assess the effects of variants in general pedigrees. We aim to compare the performance between the haplotype-based approach and the rare variant-based approach for detecting rare causal variants in pedigrees.
Extensive simulations in the sequencing setting were carried out to evaluate and compare the haplotype-based approach with the rare variant methods that drew on a more conventional collapsing strategy. As assessed through a variety of scenarios, the haplotype-based pedigree tests had enhanced statistical power compared with the rare variants based pedigree tests when the disease of interest was mainly caused by rare haplotypes (with multiple rare alleles), and vice versa when disease was caused by rare variants acting independently. For most of other situations when disease was caused both by haplotypes with multiple rare alleles and by rare variants with similar effects, these two approaches provided similar power in testing for association.
The haplotype-based approach was designed to assess the role of rare and potentially causal haplotypes. The proposed rare variants-based pedigree tests were designed to assess the role of rare and potentially causal variants. This study clearly documented the situations under which either method performs better than the other. All tests have been implemented in a software, which was submitted to the Comprehensive R Archive Network (CRAN) for general use as a computer program named rvHPDT.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior ...reports have shown that mutations in the filamin A (
FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes.
Here we report three familial cases of PH with hydrocephalus. One pedigree has a known
FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. Another pedigree demonstrated possible linkage to the Xq28 locus including
FLNA, although uncharacteristically a male was affected and sequencing of the
FLNA gene in this individual revealed no mutation. However, in the third family with an autosomal mode of inheritance, microsatellite analysis ruled out linkage with the
FLNA gene. Routine karyotyping and fluorescent in situ hybridization using BAC probes localized to
FLNA also showed no evidence of genomic rearrangement. Western blot analysis of one of the affected individuals demonstrated normal expression of the FLNA protein. Lastly, sequencing of greater than 95% of the
FLNA gene in an affected member failed to demonstrate a mutation.
In conclusion, these findings demonstrate the etiological heterogeneity of PH with hydrocephalus. Furthermore, there likely exists an autosomal PH gene, distinct from the previously described X-linked and autosomal recessive forms. Affected individuals have severe developmental delay and may have radiographic findings of hydrocephalus.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
