Biomedical subjects

Bernie Devlin

Publications and source records attributed to Bernie Devlin.

At least 19 recordsLinked to original sources

PubMed2026

Estimating protein isoform abundances with [Formula: see text].

A single gene can encode multiple versions of a protein, dubbed isoforms, with varying functionality. Cellular control of isoform abundances is critical for multiple aspects of biology and is only partially regulated by transcript levels. While long-read sequencing facilitates transcript quantification, quantifying the resulting protein isoforms on a large scale is a major challenge, complicating biological interpretation of transcript alterations. Standard "bottom up" mass spectrometry can assess only short portions of isoforms called peptides, and these peptides often map onto more than one isoform. We introduce [Formula: see text] (Protein isoform Abundance Quantification), a Bayesian method that leverages multiomic information from the peptidome and transcriptome to provide accurate estimates of isoform abundance even when peptide mapping is ambiguous. [Formula: see text] offers several advantages over existing methods in a unified framework. It provides uncertainty quantification, integrates multiomic information for improved accuracy, and provides a rigorous framework for hypothesis testing. Extensive simulations show that [Formula: see text] consistently outperforms competing methods in detecting differentially abundant protein isoforms and estimating their abundances. We use [Formula: see text] to investigate differences in isoform abundance levels between people with schizophrenia and control subjects, confirming a long-held hypothesis that levels of the C4A isoform of Complement Component 4 are increased in schizophrenia while C4B is not. These results demonstrate that [Formula: see text] can identify significant variations in isoform abundance levels not previously possible.

Protein Isoforms↗

PubMed2026

A framework to infer de novo exonic variants when parental genotypes are missing enhances association studies of autism.

MOTIVATION: Gene-damaging mutations are highly informative for studies seeking to discover genes underlying developmental disorders. Traditionally, these de novo variants are recognized by evaluating high-quality DNA sequence from affected offspring and parents. However, when parental sequence is unavailable, methods are required to infer de novo status and use this inference for association studies. RESULTS: We use data from autism spectrum disorder to illustrate and evaluate methods. Separating de novo from rare inherited variants is challenging because the latter are far more common. Using a classifier for unbalanced data and variants of known inheritance class, we build an inheritance model and then a de novo score for variants when parental data are missing. Next, we propose a new Random Draw (RD) model to use this score for gene discovery. Built into an existing inferential framework, RD produces a more powerful gene-based association test and controls the false discovery rate. AVAILABILITY AND IMPLEMENTATION: Codes are available at Github (https://github.com/HaeunM/TADA-RD) and Zenodo (DOI: https://doi.org/10.5281/zenodo.18531769).

Humans↗

PubMed2006

Novel, replicated associations between dopamine D3 receptor gene polymorphisms and schizophrenia in two independent samples.

BACKGROUND: Meta-analyses have suggested an association between schizophrenia (SZ) and a coding polymorphism (rs6280/Ser9Gly) at the dopamine D3 receptor gene (DRD3), but results have been inconsistent. Because most studies have evaluated only rs6280, the inconsistencies might reflect associations with other variants. METHODS: We analyzed polymorphisms spanning 109kb in two independent samples (United States: 13 single nucleotide polymorphisms (SNPs), 331 cases, 151 trios, 274 control subjects; India: 11 SNPs, 141 trios). RESULTS: In the U.S. samples, significant associations were detected with eight SNPs, including rs6280 (p = .001, odds ratio: 1.5). Consistent associations in the case-control and family-based analyses were detected with a common haplotype spanning intron 1 to the 3' region of the gene (rs324029-rs7625282-rs324030-rs2134655-rs10934254; case-control, p = .002; transmission disequilibrium test [TDT], p = .0009; global p-values = .002 and .007, respectively). In the Indian sample, one SNP was associated (rs10934254, p = .03). Moreover, over-transmission of the same common haplotype as the U.S. sample was observed in this cohort (TDT, p = .005; global test, p = .009). Ser9Gly (rs6280) was associated with SZ against this haplotype background but not other haplotypes. CONCLUSIONS: These data suggest previous inconsistencies might have resulted from associations with other DRD3 variants. A liability locus might be in linkage disequilibrium (LD) with or carried against, an associated haplotype 3' to rs6280. Comprehensive SNP evaluation in larger samples is needed.

Case-Control Studies↗

PubMed2006

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods.

The Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) is a multi-site, NIMH-funded study that seeks to identify genetic polymorphisms that confer susceptibility to schizophrenia among African-Americans by linkage mapping and targeted association analyses. Because deficits in certain dimensions of cognitive ability are thought to underlie liability to schizophrenia, the project also examines cognitive abilities in individuals affected by schizophrenia and their extended family members. This article describes PAARTNERS study design, ascertainment methods and preliminary sample characteristics. We aim to recruit a sample of 1260 African-American families, all of whom have at least one proband with schizophrenia or schizoaffective disorder. The data collection protocol includes a structured Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, focused neurocognitive assessment, medical records review, and the collection of blood or buccal cells for genetic analyses. We have currently completed study procedures for 106 affected sib-pair, 457 case-parent trio and 23 multiplex families. A total of 289 probands have completed the best estimate final diagnosis process and 1153 probands and family members have been administered the computerized neuropsychological battery. This project lays the foundation for future analysis of cognitive and behavioral endophenotypes. This novel integration of diagnostic, neurocognitive and genetic data will also generate valuable information for future phenotypic and genetic studies of schizophrenia.

Adult↗

PubMed2006

Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples.

BACKGROUND: Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. METHODS: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). RESULTS: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. CONCLUSIONS: Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Case-Control Studies↗

PubMed2005

Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses.

Probands with late onset Alzheimer's disease (LOAD) exhibit positive symptoms of psychosis, 30-60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimer's Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5' region of neuregulin-1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, we report results demonstrating a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. We also demonstrate that there is a significant association with a NRG1 SNP (single nucleotide polymorphism), rs392499, with ADP, chi2 = 7.0, P = 0.008. This same SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with this phenotype. Our results suggest that NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families.

Aged↗

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

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

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

Circadian phase variation in bipolar I disorder.

Abnormalities in circadian rhythms are prominent features of bipolar I disorder (BD1). To investigate circadian variation in BD1, we evaluated morningness-eveningness (M/E), a stable trait reflecting circadian phase, using the composite scale (CS) among BD1 patients (DSM IV criteria; n = 75), unscreened controls (n = 349), and patients with schizophrenia (SZ) or schizoaffective disorder (SZA) (n = 81). Our analyses showed that CS scores correlated significantly with age but did not differ by gender among the controls. BD1 patients differed significantly from controls and from SZ/SZA patients when age was considered. CS scores were distributed bi-modally among BD1 cases. There are several possible reasons for the observed heterogeneity. Younger BD1 patients, and those with rapid mood swings, were significantly more likely to have lower CS scores (i.e., to score in the 'evening' range and to have later circadian phase). CS scores were also positively correlated with the age at onset and the duration of the most severe depressive episodes. These relationships were not observed among the SZ/SZA groups. Thus, distinct patterns of M/E were noted among BD1 patients and among BD1 subgroups. The impact of medication, mood state, and chronicity on CS scores needs to be considered.

Age Factors↗

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

Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.

A recent study by Persico et al. [2001: Mol Psychiatry 6:150-159] suggests alleles of a CGG polymorphism, just 5' of the reelin gene (RELN) initiator codon, confer liability for autism, especially alleles bearing 11 or more CGG repeats (long alleles). The association is consistent across both a case-control and family-based sample. We attempted to replicate their finding using a larger, independent family-based sample from the NIH Collaborative Programs of Excellence in Autism (CPEA) Network. In our data, allele transmissions to individuals with autism versus unaffected individuals are unbiased, both when alleles are classified by repeat length and when they are classified into long/short categories. Because of the apparent linkage of autism to chromosome 7q, particularly related to the development of language, we also evaluate the relationship between Reelin alleles and the age at which autism subjects use their first word or first phrase. Neither is significantly associated with Reelin alleles. Our results are not consistent with a major role for Reelin alleles in liability to autism.

Alleles↗

PubMed2004

Haplotypes of the monoamine oxidase genes and the risk for substance use disorders.

Monoamine oxidase A (MAOA) locus is an attractive candidate for exploring genetic contribution to the variation in the risk for substance use disorders (SUD) because of its important role in the metabolism of neurotransmitters, including dopamine and serotonin. Prior findings have suggested an association of the MAOA gene with the risk for early onset SUD. To extend this research, we genotyped four MAOA markers (two VNTR polymorphisms and two SNPs) and built a cladogram reflecting the evolutionary history of MAOA haplotypes [Nguyen et al., under review]. The cladogram served as the framework for nested ANOVA and logit analyses of association between MAOA and indices of liability to SUD (diagnosis, age of onset, and a dimensional index of substance use related problems) in a sample of adult males of European ancestry. Whereas no association was found for the categorical diagnosis, a significant relationship was detected between the dimensional liability indices and MAOA haplotypes. Overall, our results, albeit not definitive, are consistent with the hypothesis that variants in MAOA account for a small portion of the variance of SUD risk, possibly mediated by liability to early onset behavioral problems.

Adult↗

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↗

PubMed2004

ADLAPH: A molecular haplotyping method based on allele-discriminating long-range PCR.

We present a method, called Allele-Discriminating Long and Accurate PCR Haplotyping (ADLAPH), for directly determining haplotypes from an extended genomic region. This method uses allele-discriminating primers in long-range PCR to amplify only one of the two chromosome homologues for the region of interest. Haplotypes are then determined from these phase-separated PCR fragments by conventional single nucleotide polymorphism (SNP) genotyping methods. This simple robust procedure makes it practical for high-throughput haplotyping of unrelated individuals, and potentially allows direct observation of haplotype information for up to 40 kb or more. We demonstrate the feasibility of this molecular haplotyping procedure by generating apolipoprotein E (APOE) haplotypes from 100 unrelated subjects.

Alleles↗

PubMed2004

Personality characteristics of women before and after recovery from an eating disorder.

BACKGROUND: Previous studies of personality characteristics in women with eating disorders primarily have focused on women who are acutely ill. This study compares personality characteristics among women who are ill with eating disorders, recovered from eating disorders, and those without eating or other Axis I disorder pathology. METHOD: Female participants were assessed for personality characteristics using the Temperament and Character Inventory (TCI): 122 with anorexia nervosa (AN; 77 ill, 45 recovered), 279 with bulimia nervosa (BN; 194 ill, 85 recovered), 267 with lifetime histories of both anorexia and bulimia nervosa (AN + BN; 194 ill, 73 recovered), 63 with eating disorder not otherwise specified (EDNOS; 31 ill, 32 recovered), and 507 without eating or Axis I disorder pathology. RESULTS: Women ill with all types of eating disorders exhibited several TCI score differences from control women, particularly in the areas of novelty-seeking, harm avoidance, self-directedness, and cooperativeness. Interestingly, women recovered from eating disorders reported higher levels of harm avoidance and lower self-directedness and cooperativeness scores than did normal control women. CONCLUSIONS: Women with eating disorders in both the ill and recovered state show higher levels of harm avoidance and lower self-directedness and cooperativeness scores than normal control women. Although findings suggest that disturbances may be trait-related and contribute to the disorders' pathogenesis, additional research with more representative community controls, rather than our pre-screened, normal controls, is needed to confirm these impressions.

Adult↗