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Silviu-Alin Bacanu

Publications and source records attributed to Silviu-Alin Bacanu.

At least 19 recordsLinked to original sources
PubMed2026

Suicidality phenotypes reflect both shared and distinct genetic factors.

Suicidality phenotypes, including suicidal ideation (SI), non-fatal suicide attempt (SA), and suicide death (SD), are heritable and exhibit both shared and phenotype-specific genetic influences. Using genomic structural equation modelling, we estimated the shared genetic architecture across GWAS of SI (176,147 cases, 1,010,300 controls), SA (53,919 cases, 1,063,988 controls), and SD (7,584 cases, 652,070 controls) and conducted a multivariate GWAS of a latent suicidality factor capturing their shared liability. This analysis identified 36 genome-wide significant loci, including seven not previously reported in any suicidality GWAS. Follow-up analyses identified residual genetic variance specific to each phenotype, including three SD-specific genomic risk loci. Conditioning suicidality phenotypes on genetic liability to psychiatric disorders revealed significant residual genetic variance across SI, SA, SD, and the suicidality common factor. Together, these results suggest that suicidality reflects both shared genetic liability and phenotype-specific contributions.

Journal Article↗
PubMed2006

Common variations in ALG9 are not associated with bipolar I disorder: a family-based study.

BACKGROUND: A mannosyltransferase gene (ALG9, DIBD1) at chromosome band 11q23 was previously identified to be disrupted by a balanced chromosomal translocation t(9;11)(p24;q23) co-segregating with bipolar affective disorder in a small family. Inborn ALG9 deficiency (congenital disorders of glycosylation type IL) is associated with progressive microcephaly, seizures, developmental delay, and hepatomegaly. It is unknown whether common variations of ALG9 predispose to bipolar affective disorder. METHODS: We tested five polymorphic markers spanning ALG9 (three intragenic and one upstream microsatellite repeats and one common missense variation, V289I (rs10502151) for their association with bipolar I disorder in two pedigree series. The NIMH (National Institute of Mental Health) pedigrees had a total of 166 families showing transmissions to 250 affected offspring, whereas The PITT (The University of Pittsburgh) pedigrees had a total of 129 families showing transmissions to 135 cases. We used transmission disequilibrium test for the association analyses. RESULTS: We identified three common and distinct haplotypes spanning the ALG9 gene. We found no statistically-significant evidence of transmission disequilibrium of marker alleles or multi-marker haplotypes to the affected offspring with bipolar I disorder. CONCLUSION: These results suggest that common variations in ALG9 do not play a major role in predisposition to bipolar affective disorder.

Journal Article↗
PubMed2005

Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates.

To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR), and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum body mass index (BMI), concern over mistakes (CM), and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.

Anorexia Nervosa↗
PubMed2005

Selection of eating-disorder phenotypes for linkage analysis.

Vulnerability to anorexia nervosa (AN) and bulimia nervosa (BN) arise from the interplay of genetic and environmental factors. To explore the genetic contribution, we measured over 100 psychiatric, personality, and temperament phenotypes of individuals with eating disorders from 154 multiplex families accessed through an AN proband (AN cohort) and 244 multiplex families accessed through a BN proband (BN cohort). To select a parsimonious subset of these attributes for linkage analysis, we subjected the variables to a multilayer decision process based on expert evaluation and statistical analysis. Criteria for trait choice included relevance to eating disorders pathology, published evidence for heritability, and results from our data. Based on these criteria, we chose six traits to analyze for linkage. Obsessionality, Age-at-Menarche, and a composite Anxiety measure displayed features of heritable quantitative traits, such as normal distribution and familial correlation, and thus appeared ideal for quantitative trait locus (QTL) linkage analysis. By contrast, some families showed highly concordant and extreme values for three variables-lifetime minimum Body Mass Index (lowest BMI attained during the course of illness), concern over mistakes, and food-related obsessions-whereas others did not. These distributions are consistent with a mixture of populations, and thus the variables were matched with covariate linkage analysis. Linkage results appear in a subsequent report. Our report lays out a systematic roadmap for utilizing a rich set of phenotypes for genetic analyses, including the selection of linkage methods paired to those phenotypes.

Algorithms↗
PubMed2005

Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Bipolar Disorder↗
PubMed2005

Linkage analysis of a completely ascertained sample of familial schizophrenics and bipolars from Palau, Micronesia.

We report on linkage analysis of a completely ascertained population of familial psychosis derived from the oceanic nation of Palau. Palau, an archipelago of islands in the Southern Pacific, currently has a population of approximately 23,000 individuals. The peoples of Palau populated these islands recently in human history, approximately 2,000 years ago. As both historical and genetic evidence suggest, the population is far more homogeneous than most other populations undergoing genetic studies, and should therefore prove quite useful for mapping genetic variants having a meaningful impact on susceptibility to psychotic disorders. Moreover, for our study, essentially all on-island schizophrenics (150) and individuals with other psychotic disorders (25) participated. By analysis of narrow (only schizophrenia) and broad (all psychosis) diagnostic schemes, two-point linkage analyses suggest that two regions of the genome harbor genetic variants affecting liability in most families, 3q28 (LOD = 3.03) and 17q32.2 (LOD = 2.80). Results from individual pedigrees also support 2q37.2, 2p14, and 17p13 as potentially harboring important genetic variants. Most of these regions have been implicated in other genetic studies of psychosis in populations physically quite distant from this Oceanic population, although some (e.g., 3q28) appear to be novel results for schizophrenia linkage analyses.

Bipolar Disorder↗
PubMed2005

Robust estimation of critical values for genome scans to detect linkage.

Estimation of study specific critical values for linkage scans (suggestive and significant thresholds) is important to identify promising regions. In this report, I propose a fast and concrete recipe for finding study specific critical values. Previously, critical values were derived theoretically or empirically. Theoretically-derived values are often conservative due to their assumption of fully informative transmissions. Empirically-derived critical values are computer and skill intensive and may not even be computationally feasible for large pedigrees. In this report, I propose a method to estimate critical values for multipoint linkage analysis using standard, widely used statistical software. The proposed method estimates study-specific critical values by using Autoregressive (AR) models to estimate the correlation between standard normal statistics at adjacent map points and then use this correlation to estimate study-specific critical values. The AR-based method is evaluated using different family structures and density of markers, under both the null hypothesis of no linkage and the alternative hypothesis of linkage between marker and disease locus. Simulations results show the AR-based method accurately predicts critical values for a wide range of study designs.

Algorithms↗
PubMed2005

Analysis of single-locus tests to detect gene/disease associations.

A goal of association analysis is to determine whether variation in a particular candidate region or gene is associated with liability to complex disease. To evaluate such candidates, ubiquitous Single Nucleotide Polymorphisms (SNPs) are useful. It is critical, however, to select a set of SNPs that are in substantial linkage disequilibrium (LD) with all other polymorphisms in the region. Whether there is an ideal statistical framework to test such a set of 'tag SNPs' for association is unknown. Compared to tests for association based on frequencies of haplotypes, recent evidence suggests tests for association based on linear combinations of the tag SNPs (Hotelling T(2) test) are more powerful. Following this logical progression, we wondered if single-locus tests would prove generally more powerful than the regression-based tests? We answer this question by investigating four inferential procedures: the maximum of a series of test statistics corrected for multiple testing by the Bonferroni procedure, T(B), or by permutation of case-control status, T(P); a procedure that tests the maximum of a smoothed curve fitted to the series of of test statistics, T(S); and the Hotelling T(2) procedure, which we call T(R). These procedures are evaluated by simulating data like that from human populations, including realistic levels of LD and realistic effects of alleles conferring liability to disease. We find that power depends on the correlation structure of SNPs within a gene, the density of tag SNPs, and the placement of the liability allele. The clearest pattern emerges between power and the number of SNPs selected. When a large fraction of the SNPs within a gene are tested, and multiple SNPs are highly correlated with the liability allele, T(S) has better power. Using a SNP selection scheme that optimizes power but also requires a substantial number of SNPs to be genotyped (roughly 10-20 SNPs per gene), power of T(P) is generally superior to that for the other procedures, including T(R). Finally, when a SNP selection procedure that targets a minimal number of SNPs per gene is applied, the average performances of T(P) and T(R) are indistinguishable.

Computer Simulation↗
PubMed2005

Characterization of multilocus linkage disequilibrium.

Linkage disequilibrium (LD) in the human genome, often measured as pairwise correlation between adjacent markers, shows substantial spatial heterogeneity. Congruent with these results, studies have found that certain regions of the genome have far less haplotype diversity than expected if the alleles at multiple markers were independent, while other sets of adjacent markers behave almost independently. Regions with limited haplotype diversity have been described as "blocked" or "haplotype blocks." In this article, we propose a new method that aims to distinguish between blocked and unblocked regions in the genome. Like some other approaches, the method analyses haplotype diversity. Unlike other methods, it allows for adjacent, distinct blocks and also multiple, independent single nucleotide polymorphisms (SNPs) separating blocks. Based on an approximate likelihood model and a parsimony criterion to penalize for model complexity, the method partitions a genomic region into blocks relatively quickly, and simulations suggest that its partitions are accurate. We also propose a new, efficient method to select SNPs for association analysis, namely tag SNPs. These methods compare favorably to similar blocking and tagging methods using simulations.

Algorithms↗
PubMed2005

Multipoint linkage analysis for a very dense set of markers.

Multipoint linkage methods are powerful tools that are often employed as the first means to discover alleles affecting liability to diseases. With the advent of dense marker maps, linkage disequilibrium (LD) between markers is inevitable and it comes at the cost of bias and an increased rate of false-positive findings for linkage analyses that assume alleles of different markers are independent. I propose a "multipoint on subsets" method that avoids this issue by partitioning the markers into interlaced and non-overlapping subsets. Each subset is analyzed separately, their statistics are then averaged, and the resulting average is standardized by its estimated standard deviation. In addition to being robust to the challenges induced by dependent marker alleles, data simulated under linkage equilibrium show that the proposed method does not suffer any detectable loss of power when compared to traditional methods.

Alleles↗
PubMed2005

Association of multiple DRD2 polymorphisms with anorexia nervosa.

To investigate whether the dopaminergic system plays a role in the etiology of anorexia nervosa (AN) via the dopamine D2 receptor, we investigated association and transmission disequilibrium at seven single-nucleotide polymorphisms (SNPs) spanning about 75 kbp of the gene DRD2. We studied 191 probands with a DSM-IV diagnosis of AN, 457 parents and affected relatives with a DSM-IV eating disorder diagnosis, and 98 unrelated, female, normal weight controls. The -141 C/- insertion/deletion (-141 Indel), previously shown to affect DRD2 transcription efficiency, and multiple exon seven polymorphisms, one of which has previously been shown to affect DRD2 transcript stability, exhibited statistically significant association with diagnosis in haplotype transmission disequilibrium and in haplotype case : control analyses. Significant linkage disequilibrium between the -141 Indel and two exon seven SNPs (939Y and 957Y) was observed over a distance of >50 kbp in the AN probands but not in the controls. Genetically transmitted variation in D2 dopamine receptor expression mediated by functional polymorphisms affecting transcription and translation efficiency may play a role in vulnerability to AN.

Adolescent↗
PubMed2005

Heritability of psychosis in Alzheimer disease.

OBJECTIVE: The authors have previously demonstrated familial clustering of psychotic symptoms in late-onset Alzheimer disease (LOAD+P) and sought to estimate and explore the nature of the heritability of LOAD+P. METHODS: The heritability of LOAD+P, defined by single and multiple psychotic symptoms, was estimated with data from the National Institute of Mental Health AD Genetics Initiative. RESULTS: The estimated heritability for LOAD+P defined by multiple psychotic symptoms was 61%; for LOAD+P defined by any occurrence of psychotic symptoms, it was 30%. CONCLUSION: Multiplicity of symptoms may represent a useful means for defining a genetically determined LOAD+P phenotype.

Aged↗
PubMed2004

Genetic analysis of bulimia nervosa: methods and sample description.

OBJECTIVE: Twin and family studies suggest that genetic variants contribute to the pathogenesis of bulimia nervosa (BN) and anorexia nervosa (AN). The Price Foundation has supported an international, multisite study of families with these disorders to identify these genetic variations. The current study presents the clinical characteristics of this sample as well as a description of the study methodology. METHOD: All probands met modified criteria for BN or bulimia nervosa with a history of AN (BAN) as defined in the 4th ed. of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994). All affected relatives met DSM-IV criteria for BN, AN, BAN, or eating disorders not otherwise specified (EDNOS). Probands and affected relatives were assessed diagnostically using both trained-rater and self-report assessments. DNA samples were collected from probands, affected relatives, and available biologic parents. RESULTS: Assessments were obtained from 163 BN probands and 165 BAN probands. Overall, there were 365 relative pairs available for linkage analysis. Of the affected relatives of BN probands, 62 were diagnosed as BN (34.8%), 49 as BAN (27.5%), 35 as AN (19.7%), and 32 as EDNOS (18.0%). For the relatives of BAN probands, 42 were diagnosed as BN (22.5%), 67 as BAN (35.8%), 48 as AN (25.7%), and 30 as EDNOS (16.0%). DISCUSSION: This study represents the largest genetic study of eating disorders to date. Clinical data indicate that although there are a large number of individuals with BN disorders, a range of eating pathology is represented in the sample, allowing for the examination of several different phenotypes in molecular genetic analyses.

Anxiety↗
PubMed2004

Personality in men with eating disorders.

OBJECTIVE: This study compares personality variables of men with eating disorders to women with eating disorders. METHOD: Data were obtained from an international study of the genetics of eating disorders. Forty-two male participants were age-band matched at 1:2 ratio to females from the same study. Personality features were compared between males and females controlling for diagnostic subgroup. RESULTS: Males with eating disorders appear to be slightly less at risk for perfectionism, harm avoidance, reward dependence, and cooperativeness than females. Few differences were found when diagnostic subgroup was considered. CONCLUSION: Observed differences in personality variables may help explain the difference in incidence and prevalence of eating disorders in men and women.

Adult↗
PubMed2003

Heritability of fearful-anxious endophenotypes in infant rhesus macaques: a preliminary report.

BACKGROUND: Research efforts to discover the genetic underpinnings of anxiety and depression is challenging because of the etiologic heterogeneity inherent to these disorders. These efforts might be aided by the study of related behavioral phenotypes in model organisms, such as monkeys. METHODS: Eighty-five rhesus monkeys (Macaca mulatta) from the Oregon National Primate Research Center were drawn from a standard matriarchal colony and tested for behavioral response in four testing paradigms designed to elicit fearful-anxious reactions. Heritabilities were estimated using variance component-based quantitative genetic analyses with much of the genetic information arising from paternal half-sibs. RESULTS: Individual behaviors reflecting increased distress responses (e.g., vocalizations and teeth grinding) and behavioral inhibition (e.g., latency to leave mother, latency to inspect novel fruit) showed significant heritability, even though a small number of monkeys were assessed. Exploratory factor analyses identified seven clusters of behaviors across tests, some of which were found to be heritable. CONCLUSIONS: These results indicate that several specific fearful-anxious behaviors in infant rhesus monkeys are heritable within this colony. Accordingly, these phenotypes, which are believed to represent the genetic liability for anxiety and depression, are good candidates for further genetic investigation in this population.

Animals↗
PubMed2002

Significant linkage on chromosome 10p in families with bulimia nervosa.

Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to contribute substantially to the observed familiality. In turn, behavioral components of BN, such as self-induced vomiting, are reliably measured and heritable. To identify regions of the genome harboring genetic variants conferring susceptibility to BN, we conducted a linkage analysis of multiplex families with eating disorders that were identified through a proband with BN. Linkage analysis of the entire sample of 308 families yielded a double peak, with the highest nonparametric multipoint maximum LOD score (MLS), of 2.92, on chromosome 10. Given the high heritability of self-induced vomiting and the reliability with which it can be measured, we performed linkage analysis in a subset (n=133) of families in which at least two affected relatives reported a symptom pattern that included self-induced vomiting. The highest MLS (3.39) observed was on chromosome 10, between markers D10S1430 and D10S1423. These results provide evidence of the presence of a susceptibility locus for BN on chromosome 10p. Using simulations, we demonstrate that both of these scores, 2.92 and 3.39, meet the widely accepted criterion for genomewide significance. Another region on 14q meets the criterion for genomewide suggestive linkage, with MLSs of 1.97 (full sample) and 1.75 (subset) at 62 centimorgans from p-ter.

Bulimia↗
PubMed2002

Linkage analysis of anorexia nervosa incorporating behavioral covariates.

Eating disorders, such as anorexia nervosa (AN) and bulimia nervosa (BN), have genetic and environmental underpinnings. To explore genetic contributions to AN, we measured psychiatric, personality and temperament phenotypes of individuals diagnosed with eating disorders from 196 multiplex families, all accessed through an AN proband, as well as genotyping a battery of 387 short tandem repeat (STR) markers distributed across the genome. On these data we performed a multipoint affected sibling pair (ASP) linkage analysis using a novel method that incorporates covariates. By exploring seven attributes thought to typify individuals with eating disorders, we identified two variables, drive-for-thinness and obsessionality, which delimit populations among the ASPs. For both of these traits, or covariates, there were a cluster of ASPs who have high and concordant values for these traits, in keeping with our expectations for individuals with AN, and other clusters of ASPs who did not meet those expectations. When we incorporated these covariates into the ASP linkage analysis, both jointly and separately, we found several regions of suggestive linkage: one close to genome-wide significance on chromosome 1 (at 210 cM, D1S1660; LOD = 3.46, P = 0.00003), another on chromosome 2 (at 114 cM, D2S1790; LOD = 2.22, P = 0.00070) and a third region on chromosome 13 (at 26 cM, D13S894; LOD = 2.50, P = 0.00035). By comparing our results to those implemented using more standard linkage methods, we find the covariates convey substantial information for the linkage analysis.

Anorexia Nervosa↗