Search

Many statistical tests rely on the assumption that the residuals of a model are normally distributed. Rank-based inverse normal transformation (INT) of the dependent variable is one of the most popular approaches to satisfy the normality assumption. When covariates are included in the analysis, a common approach is to first adjust for the covariates and then normalize the residuals. This study investigated the effect of regressing covariates against the dependent variable and then applying rank-based INT to the residuals. The correlation between the dependent variable and covariates at each stage of processing was assessed. An alternative approach was tested in which rank-based INT was applied to the dependent variable before regressing covariates. Analyses based on both simulated and real data examples demonstrated that applying rank-based INT to the dependent variable residuals after regressing out covariates re-introduces a linear correlation between the dependent variable and covariates, increasing type-I errors and reducing power. On the other hand, when rank-based INT was applied prior to controlling for covariate effects, residuals were normally distributed and linearly uncorrelated with covariates. This latter approach is therefore recommended in situations were normality of the dependent variable is required.

Among the many candidate genes analyzed in eating disorder (ED) patients, those involved in dopaminergic functions may be of special relevance, as dopamine is known to play a significant role in feeding behavior, the distortion of body image, hyperactivity and reward and reinforcement processes. We aimed to determine the effect of functional polymorphisms and haplotypes in the Dopamine Receptor D4 (DRD4) gene on general psychopathological symptoms in ED patients. Two-hundred-and-seventy-three ED patients [199 with Anorexia Nervosa (AN) and 74 with Bulimia Nervosa (BN)] completed the SCL-90R inventory and were genotyped for four functional, clinically relevant DRD4 polymorphisms: three variants in the promoter region [120-bp tandem repeat (TR, long vs. short allele), C-616G and C-521 T] and a variable number of tandem repeats (VNTR) in exon 3 (7R vs. non-7R allele). After correcting for multiple testing, none of the assayed polymorphisms were individually associated with SCL-90R results. Four DRD4 haplotypes (*1-*4) were detected in the patients with a frequency > 0.1. In the BN group, haplotype *2 (non7R-TR long-C-C) was associated with higher scores in the three global SCL-90R indices (GSI, PSDI and PST) after Bonferroni correction (p ≤ 0.01 in all instances). Furthermore, carriers of this haplotype displayed higher scores (worst symptomatology) in Somatization, Obsessive-Compulsive, Anxiety, Phobic anxiety, Paranoid ideation and the test additional items (p-values for the differences between carriers vs. non-carriers ranging from 0.0001 to 0.0110). Certain combinations of DRD4 variants may contribute to psychopathological features in BN patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The psychological effects of brain-expressed imprinted genes in humans are virtually unknown. Prader-Willi syndrome (PWS) is a neurogenetic condition mediated by genomic imprinting, which involves high rates of psychosis characterized by hallucinations and paranoia, as well as autism. Altered expression of two brain-expressed imprinted genes, MAGEL2 and NDN , mediates a suite of PWS-related phenotypes, including behaviour, in mice. We phenotyped a large population of typical individuals for schizophrenia-spectrum and autism-spectrum traits, and genotyped them for the single-nucleotide polymorphism rs850807, which is putatively functional and linked with MAGEL2 and NDN Genetic variation in rs850807 was strongly and exclusively associated with the ideas of reference subscale of the schizophrenia spectrum, which is best typified as paranoia. These findings provide a single-locus genetic model for analysing the neurological and psychological bases of paranoid thinking, and implicate imprinted genes, and genomic conflicts, in human mentalistic thought., (© 2018 The Author(s).)

Psychotic disorders and major depression, both typically adult-onset conditions, often co-occur. At younger ages psychotic experiences and depressive symptoms are often reported in the community. We used a genetically sensitive longitudinal design to investigate the relationship between psychotic experiences and depressive symptoms in adolescence. A representative community sample of twins from England and Wales was employed. Self-rated depressive symptoms, paranoia, hallucinations, cognitive disorganization, grandiosity, anhedonia, and parent-rated negative symptoms were collected when the twins were age 16 (N = 9618) and again on a representative subsample 9 months later (N = 2873). Direction and aetiology of associations were assessed using genetically informative cross-lagged models. Depressive symptoms were moderately correlated with paranoia, hallucinations, and cognitive disorganization. Lower correlations were observed between depression and anhedonia, and depression and parent-rated negative symptoms. Nonsignificant correlations were observed between depression and grandiosity. Largely the same genetic effects influenced depression and paranoia, depression and hallucinations, and depression and cognitive disorganization. Modest overlap in environmental influences also played a role in the associations. Significant bi-directional longitudinal associations were observed between depression and paranoia. Hallucinations and cognitive disorganization during adolescence were found to impact later depression, even after controlling for earlier levels of depression. Our study shows that psychotic experiences and depression, as traits in the community, have a high genetic overlap in mid-adolescence. Future research should test the prediction stemming from our longitudinal results, namely that reducing or ameliorating positive and cognitive psychotic experiences in adolescence would decrease later depressive symptoms., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Aim: The present study employed Experience Sampling Methodology to examine whether the interaction between childhood bullying and FKBP5 variability (i) is associated with the expression of psychotic-like experiences, paranoia, and negative affect, and (ii) moderates psychotic-like, paranoid, and affective reactivity to different forms of momentary stress (situational and social) in daily life., Methods: A total of 206 nonclinical young adults were interviewed for bullying with the Childhood Experience of Care and Abuse and were prompted randomly eight times daily for one week to complete assessments of their current experiences, affect, and stress appraisals. Participants were genotyped for three FKBP5 single nucleotide polymorphisms (SNPs) (rs3800373, rs9296158, and rs1360780) that have been linked to hypothalamus-pituitary-adrenal axis reactivity. Multilevel analyses were conducted to examine the effect of the interaction between childhood bullying and the FKBP5 haplotype derived from these three SNPs., Results: The interaction between bullying and the FKBP5 haplotype was associated with positive, but not negative, psychotic-like experiences, paranoia, and negative affect. The bullying x FKBP5 interaction also moderated the association of a social stress appraisal (specifically, being alone because people do not want to be with you) with psychotic-like experiences and negative affect in daily life. Simple slopes analyses indicated that, in all cases, the associations were significantly increased by exposure to bullying in participants with the risk haplotype, but not for those with the non-risk haplotype., Discussion: The present study provides the first evidence of the interplay between childhood bullying and FKBP5 variability in the real-world expression of psychosis proneness and social stress reactivity. The findings underscore the importance of investigating how gene-environment interactions are involved in mechanistic pathways to the extended psychosis phenotype and lend further support to the increasing relevance given to socially defeating appraisals in the experience of reality distortion.

Background: Chromosomal region 7q21.3 comprises approximately 5.2 mega base pairs that include genes DLX5/6, SHFM1, and DYNC1I1 associated with split hand/split foot malformation 1. So far, there are reports of eight families with deletion of DYNC1I1 and preserved DLX5/6 associated with ectrodactyly. From these families, only three patients did not present ectrodactyly and, unlike our patient, no other cases have been described as having craniofacial dysmorphology, mitral valve prolapse, kyphoscoliosis, inguinal herniae, or personality disorder. There is no designation described in the literature for patients with syndromic manifestations without ectrodactyly, which hinders diagnosis., Case Presentation: We report the case of a 44-year-old mestizo (combined European and Amerindian descent) man with a 3191 kilo base pairs deletion and International System for Human Cytogenetic Nomenclature array 7q21.3 (93,389,222-96,579,845)x1. Clinical manifestations included micrognathia, retrognathia, wormian bones, auditory canal stenosis, depressed nasal bridge, epicanthal fold, fullness of upper eyelid, long philtrum, low-set ears, sensorineural hearing loss, kyphoscoliosis, bilateral inguinal herniae, mild mitral valve prolapse, and paranoid personality disorder. His isolated DNA was analyzed using a CytoScan HD Microarray system. Chromosome Analysis Suite software was utilized for the microarray analysis. All copy number changes were determined using the human genome build 19 (hg19/NCBI build 37)., Conclusions: Cases of deletions within chromosome 7q21.3 that include the split hand/split foot malformation 1 region represent a diagnostic challenge when not presenting ectrodactyly despite being syndromic. Due to the heterogeneity of the region, a better method to group and classify these patients is needed to facilitate their clinical diagnosis. For this purpose, we suggest that patients with 7q21.3 deletion including DYNC1I1 and preserved DLX5/6 without ectrodactyly, accompanied by craniofacial dysmorphology, personality disorder, hearing loss, musculoskeletal disorder, inguinal herniae and/or mitral valve prolapse be referred to by the eponym Ramos-Martínez syndrome.

Background: Bullying is a risk factor for developing psychotic experiences (PEs). Whether bullying is associated with particular PEs, and the extent to which genes and environments influence the association, are unknown. This study investigated which specific PEs in adolescence are associated with earlier bullying victimization and the genetic and environmental contributions underlying their association., Method: Participants were 4826 twin pairs from a longitudinal community-based twin study in England and Wales who reported on their bullying victimization at the age of 12 years. Measures of specific PEs (self-rated Paranoia, Hallucinations, Cognitive disorganization, Grandiosity, Anhedonia, and parent-rated Negative Symptoms) were recorded at age of 16 years., Results: Childhood bullying victimization was most strongly associated with Paranoia in adolescence (r = .26; P < .01), with weaker associations with Hallucinations, Cognitive Disorganization, parent-rated Negative Symptoms (r = .12-.20; P < .01), Grandiosity (r = .04; P < .05), and Anhedonia (r = .00, n.s.). Bivariate twin model-fitting demonstrated that bullying victimization and Paranoia were both heritable (35% and 52%, respectively) with unique environmental influences (39% and 48%, respectively), and bullying victimization showed common environmental influences (26%). The association between bullying victimization and Paranoia operated almost entirely via genetic influences (bivariate heritability = 93%), with considerable genetic overlap (genetic correlation = .55)., Conclusion: In contrast to the assumed role of bullying victimization as an environmental trigger, these data suggest that bullying victimization in late childhood is particularly linked to self-rated Paranoia in adolescence via a shared genetic propensity. Clinically, individuals with a history of bullying victimization are predicted to be particularly susceptible to paranoid symptoms., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

We report a genome-wide association study (GWAS) for cocaine dependence (CD) in three sets of African- and European-American subjects (AAs and EAs, respectively) to identify pathways, genes and alleles important in CD risk. The discovery GWAS data set (n=5697 subjects) was genotyped using the Illumina OmniQuad microarray (8 90 000 analyzed single-nucleotide polymorphisms (SNPs)). Additional genotypes were imputed based on the 1000 Genomes reference panel. Top-ranked findings were evaluated by incorporating information from publicly available GWAS data from 4063 subjects. Then, the most significant GWAS SNPs were genotyped in 2549 independent subjects. We observed one genome-wide-significant (GWS) result: rs2629540 at the FAM53B ('family with sequence similarity 53, member B') locus. This was supported in both AAs and EAs; P-value (meta-analysis of all samples)=4.28 × 10(-8). The gene maps to the same chromosomal region as the maximum peak we observed in a previous linkage study. NCOR2 (nuclear receptor corepressor 2) SNP rs150954431 was associated with P=1.19 × 10(-9) in the EA discovery sample. SNP rs2456778, which maps to CDK1 ('cyclin-dependent kinase 1'), was associated with cocaine-induced paranoia in AAs in the discovery sample only (P=4.68 × 10(-8)). This is the first study to identify risk variants for CD using GWAS. Our results implicate novel risk loci and provide insights into potential therapeutic and prevention strategies.

Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level.

Background: Personality correlates highly with both cocaine and nicotine dependencies (CD, ND), and their co-morbid psychopathologies. However, little is known about the nature of these relationships. This study examined if environment (marriage) or genetics (a single SNP, CHRNA5*rs16969968) would moderate the correlation of personality with CD, ND and cocaine-induced paranoia (CIP) in African and European Americans (AAs, EAs)., Methods: 1432 EAs and 1513 AAs were examined using logistic regression. Personality was assessed by NEO-PI-R, while CD, ND and CIP were diagnosed according to DSM-IV. ND and CD were examined as binary traits and for the analysis of CIP, subjects were divided into 3 groups: (A) Controls with no CIP; (B) CD cases without CIP; and (C) CD cases with CIP. Multiple testing was Bonferroni-corrected., Results: For CD and ND in the EA population, marital status proved to be a significant moderator in their relationship with openness only (OR = 1.90, 95%CI = 1.36-2.64, p = 1.54e-04 and OR = 2.12, 95%CI = 1.52-2.90, p = 4.65e-06 respectively). For CIP, marriage was observed to moderate its correlation with openness and neuroticism (OR = 1.39, 95%CI = 1.18-1.63, p = 7.64e-04 and OR = 1.26, 95%CI = 1.12-1.42, p = 1.27e-03 respectively). The correlations moderated by rs16969968 were those of conscientiousness and CD (OR = 1.62, 95%CI: 1.23-2.12, p = 8.94e-04) as well as CIP (OR = 1.21, 95%CI: 1.11-1.32, p = 4.93e-04 when comparing group A versus group C). No significant interactions were observed in AA population. The Bonferroni-corrected significance threshold was set to be 1.67e-03., Conclusion: The role of personality in CD and CIP may be interceded by both environment and genetics, while in ND by environment only.

We recently reported that, in a European-American (EA) sample, the interaction between two cannabinoid receptor 1 gene (CNR1) variants significantly increased risk for drug dependence (DD), including cocaine dependence (CD). This study aimed to investigate directly the association between CNR1 and CD in four independent samples. Eight markers across the 45 kb CNR1 region and four large samples, ie, family-based European-American (EA) sample (n=734), case-control EA sample (n=862), family-based African-American (AA) sample (n=834) and case-control AA sample (n=619) were examined in the present study. We investigated the association of these markers with CD and cocaine-induced paranoia (CIP) in the EA family sample first, and then replicated positive results in the other three samples. The interaction between two independent CNR1 variants, ie, the G allele-containing genotypes of rs6454674 (SNP3(G+)), and the T/T genotype of rs806368 (SNP8(T)/T), significantly increased risk for CD in the EA family (P(GEE)=0.015) and EA case-control (P(regression)=0.003) samples. EA subjects with SNP3(G+) and SNP8(T)/T had higher risk to develop CD than those EA subjects with the other genotypes for these two SNPs (LR+ =1.4). The SNP3(G)-SNP8(T)haplotype also showed significant association (P=0.018) with CD in the EA case-control sample. SNP8-containing haplotypes showed significant association with both CD (P(global)=0.007) and CIP (P(global)=0.003) in the EA family sample. In the AA family sample, SNP8(T)/T significantly conferred higher risk for CD (P=0.019). We conclude that two independent CNR1 variants have significant interaction effects on risk for CD in EAs; they may also have effects on risk for CD in AAs.

It has been suggested that genes impact on the degree to which minor daily stressors cause variation in the intensity of subtle paranoid experiences. The objective of the present study was to test the hypothesis that catechol-O-methyltransferase (COMT) Val(158)Met and brain-derived neurotrophic factor (BDNF) Val(66)Met in part mediate genetic effects on paranoid reactivity to minor stressors. In a general population sample of 579 young adult female twins, on the one hand, appraisals of (1) event-related stress and (2) social stress and, on the other hand, feelings of paranoia in the flow of daily life were assessed using momentary assessment technology for five consecutive days. Multilevel regression analyses were used to examine moderation of daily life stress-induced paranoia by COMT Val(158)Met and BDNF Val(66)Met genotypes. Catechol-O-methyltransferase Val carriers displayed more feelings of paranoia in response to event stress compared with Met carriers. Brain-derived neurotrophic factor Met carriers showed more social-stress-induced paranoia than individuals with the Val/Val genotype. Thus, paranoia in the flow of daily life may be the result of gene-environment interactions that can be traced to different types of stress being moderated by different types of genetic variation.

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.

In this communication, we describe two cases of proximal 2q trisomy (2q11.2--> q21.1) resulting from an interchromosomal insertion. The chromosomal origin of the insertion was confirmed by fluorescence in situ hybridisation. An unbalanced karyotype, 46,XX,der(8) ,ins(8;2) (p21.3; q21.1q11.2), was found in the proband and her mother, who both have mild mental retardation, short stature, dysmorphic features, insulin dependent diabetes mellitus, and a psychotic illness. This family is a rare example of direct transmission of a partial autosomal trisomy.

Paranoia in the context of cocaine abuse is common and potentially dangerous. Several lines of evidence suggest that this phenomenon may be related to function of the dopamine transporter protein (DAT). DAT is the site of presynaptic reuptake of dopamine, an event that terminates its synaptic activity. The gene coding for dopamine transporter protein (DAT1) contains a variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region that can be typed by the polymerase chain reaction (PCR) (Vandenbergh et al. 1992). Although this is not a coding region polymorphism, it is close to the coding region and could plausibly be in linkage disequilibrium with a mutation in the gene. Cocaine blocks the dopamine transporter and increases synaptic availability of dopamine. We examined DAT alleles in 58 white and 45 black cocaine users in order to test only two hypotheses: (1) Is there an allelic association between DAT and cocaine dependence? and (2) Is there an allelic association between DAT and cocaine-induced paranoia? We did not demonstrate an allelic association with cocaine dependence. However, within the white sample, DAT genotype was associated with cocaine-induced paranoia (allele frequency for allele 9 = .16 for those without paranoid experiences versus .35 for those with, chi 2 = 3.9 [2 x 2 table], p < .05). There was no significant difference for the same measure in the black sample. Certain DAT genotypes may therefore predispose to paranoia in the context of cocaine use in white populations. We caution that these results require independent replication.

Genetic and biochemical findings in paranoid schizophrenia and other paranoid psychoses are reviewed. Although the data suggesting a lower genetic loading for schizophrenia in paranoid versus nonparanoid schizophrenia are unclear, paranoid schizophrenia does, to a limited extent, breed true within families. Monozygotic twins concordant for schizophrenia tend to be either both paranoid or both nonparanoid schizophrenics. In all studies, the risk for schizophrenia in the relatives of patients with paranoid psychosis is close to that found in the normal population. Genetic studies provide no evidence for a link between affective illness and either paranoid schizophrenia or paranoid psychosis. Although reports of low platelet monoamine oxidase activity in paranoid schizophrenia have not been confirmed, recent results suggest that brain norepinephrine levels may be higher in paranoid than in nonparanoid schizophrenics. Genetic and biochemical findings suggest some differences between paranoid and nonparanoid schizophrenia, but definitive clarification of the relationship between these two syndromes must await future research. From a genetic perspective, paranoid psychosis appears to bear little relationship to schizophrenia.

In a genetic study of the first-degree relatives of 77 patients with delusional (paranoid) psychoses, the morbidity risks for schizophrenia, affective disorders, and atypical psychoses were evaluated using ICD-9 criteria. The prevalence of schizophrenia was 3.10 percent (4.12 percent with age correction to 40 years and 4.94 percent with age correction to age 60), which is higher than in investigations of paranoid psychoses, but lower than in studies of paranoid schizophrenia. The prevalence figure for affective disorders (age-corrected 3.04 percent for unipolar plus bipolar patients) is also intermediate to those for relatives of paranoid schizophrenics and paranoid psychotics. When the 77 index delusional patients were subdivided into axial syndromes (endogenomorphic-schizophrenic, endogenomorphic-cyclothymic, and organomorphic axial syndromes), two very homogeneous subgroups emerged. The endogenomorphic-schizophrenic subgroup showed high rates of schizophrenic secondary cases, whereas the endogenomorphic-cyclothymic subgroup showed high rates of affectively disordered secondary cases. The third organomorphic subgroup showed a high prevalence of atypical psychoses among first-degree relatives. Thirty-seven of the 77 index patients could not be assigned to any axial syndrome; their first-degree relatives had an increased prevalence of schizophrenia, but affective disorders were no more frequent than in the normal population. These data suggest that the heterogeneous group of paranoid psychoses can be meaningfully subdivided by use of axial syndromes which are viewed as representing "basic" disturbances underlying delusional symptomatology.

A new mathematical model for quantification of familial factors was used in this study of psychiatric morbidity among the first-degree relatives of 25 patients with paranoid psychosis. The method provides a measure, a familial score of psychiatric morbidity of practical value in correlation analysis since it is applicable at different numbers of relatives per proband, excludes the influence of systematical errors, and allows the inclusion of background factors. A total of 159 first-degree relatives above the age of 15 were traced, 44 (28%) of whom were found to have a history of psychiatric disorder. The familial score of psychiatric morbidity, which varied between 2.0 and 23.0 in the 25 patients, was not significantly correlated to neurophysiological findings or clinical picture. A highly significant negative correlation between the familial score and parental age suggested that the relative influence of nonfamilial factors on the development of psychiatric disorder may be increased with increasing parental age.