Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Personality traits as an endophenotype in genetic studies on suicidality in bipolar disorder.

Introduction The influence of personality traits on suicidal behaviour risk has been well documented. Personality traits and suicidal behaviour are partially genetically determined and personality has been described as an endophenotype of suicidal behaviour. The aim of this study was to investigate a possible association between personality traits with suicidal behaviour and selected serotonergic gene polymorphisms. METHODS: In the study we included 156 patients meeting DSM-IV criteria for bipolar disorder (BP) and 93 healthy controls. The personality dimensions were assessed using the Temperament and Character Inventory (TCI). We genotyped two selected polymorphisms of the tryptophan hydroxylase 1 (TPH1) gene (rs1800532 218A>C and rs1799913 779A>C) and polymorphism in the promoter region of serotonin transporter gene (5-HTTLPR, rs25531) related to serotoninergic neurotransmission. Multiple poisson regression, logistic regression and Kruskal-Wallis tests were applied. RESULTS: We found numerous differences between the BP patients and the control group in terms of their TCI dimensions/subdimensions. Significant differences were found between patients with, and without, suicidal attempts in fatigability and asthenia (Ha4), as well as in harm avoidance (Ha). We also found that the interactions between TCI subdimensions (the interaction of disordiness (Ns4) and spiritual acceptance (St3), disordiness (Ns4) and integrated conscience (C5), extravagance (Ns3) and resourcefulness (Sd3)) were significantly contributing for suicidal behaviour risk. We found association between all studied genetic polymorphisms and several TCI dimensions and subdimensions. CONCLUSION: Our results confirm that personality traits are partially determined by genes. Both personality traits and the interactions between temperament and character traits, may be helpful in predicting suicidal behaviour.

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe.

Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n=11 540; P=3.89 × 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23 206 independent samples of European ancestry (P=0.0029, OR=1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.

Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) has been involved in the pathogenesis of bipolar mood disorder and in the mechanism of mood-normalizing action of lithium. The aim of this study was to find a possible association between lithium prophylactic effect in bipolar patients and two polymorphisms of BDNF gene. METHODS: Eighty-eight patients (35 males, 53 females) with bipolar illness were studied. Duration of lithium prophylaxis ranged between 5-27 years (mean 15 years). Three categories of prophylactic lithium response were delineated: excellent responders (ER), partial responders (PR) and non-responders (NR). All patients were genotyped for two polymorphisms of BDNF gene: Val66Met and -270C/T. RESULTS: The Val/Met genotype of Val66Met polymorphism occurred more frequently (p = 0.037) and there was a trend for a higher incidence of Met allele (p = 0.076), in ER than in NR. A trend for C/T genotype and T allele of -270C/T polymorphism was observed to occur more frequently in ER than in NR (p = 0.057 and p = 0.065, respectively). CONCLUSION: The data obtained suggest that polymorphism of BDNF gene may be connected with a quality of lithium prophylaxis.

An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia.

Dopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed.

Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects.

Altered dopamine neurotransmission and eye movement disturbances have been implicated in the pathogenic process of schizophrenia. So far, molecular genetic studies have shown little association between schizophrenia and polymorphism of any dopamine receptor or transporter genes except for some findings concerning D3 receptor (DRD3) gene. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives and they have been suggested as a phenotypic marker in genetic studies of this illness. Here we report an association between the Ser9Gly polymorphism of the DRD3 gene and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 119 schizophrenic patients and in 94 unrelated healthy control subjects. In schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was highest in individuals with the Ser-Ser genotype, significantly lower in Ser-Gly and lowest in the Gly-Gly genotype. The Ser-Ser genotype was more prevalent in patients with a higher intensity of both fixation (58.1 vs 23.9% P < 0.001) and smooth pursuit disturbances (52.3 vs 25.8%, P < 0.02) and the Ser-Gly genotype frequency was lower in patients with higher fixation disturbances (37.0 vs 60.9%, P < 0.02). In control subjects, the genotype frequency Ser-Ser was higher in subjects with any degree of eye movement disturbances compared to subjects without such disturbances both for fixation and smooth pursuit performance (81.0 vs 50.7%, P < 0.05 and 79.2 vs 50.0%, P < 0.05, respectively). In control subjects the frequency of Ser-Gly was lower in the first group, for either fixation or smooth pursuit, compared to normal performers (9.5 vs 43.8%, P < 0.01 and 8.3 vs 45.7, P < 0.005, respectively). We suggest that the DRD3 Ser9Gly polymorphism may be a contributing factor to the performance of eye movements used as a phenotypic marker of schizophrenia.

Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationship to temperamental dimensions measured by the Temperament and Character Inventory in healthy volunteers.

There is evidence for an association between polymorphisms of monoamine transporter genes and temperamental personality traits. Recent findings have shown that interaction of allelic variants of the different genes may contribute to the personality factors. We studied the association between temperamental personality dimensions measured with the Temperament and Character Inventory (TCI) and polymorphisms of the dopamine (DAT), norepinephrine (NET) and serotonin (5-HTT) transporter genes in 127 healthy Polish volunteers. There were no significant differences between means of TCI temperamental dimensions (novelty seeking, reward dependence, persistence and harm avoidance) and the transporter genes compared by ANOVA. There were some significant associations between genotypes and TCI subdimensions. Individuals carrying the A9/A9 DAT genotype have lower RD4 scores (dependence vs. independence) than A10/A10 individuals (3.0 +/- 1.4 vs. 3.5 +/- 1.3); p = 0.01. Examining 5-HTT gene promoter polymorphism, heterozygous individuals (l/s) and individuals with 44-bp deletion (s/s) scored significantly lower in the HA1 subdimension (anticipatory worry and pessimism vs. uninhibited optimism; 4.3 +/- 2.3 vs. 5.5 +/- 2.6) in comparison with individuals without deletion (l/l); p = 0.021. The NET transporter gene polymorphism showed no significant association with any of the temperamental TCI subdimensions.

[Genetic factors in the etiology of anorexia nervosa]. / Czynniki genetyczne w etiologii jadlowstretu psychicznego.

Anorexia nervosa (AN) is a disease of complex ethiopatogenesis. Population genetics studies suggest a significant role of genetic factors in the morbidity risk. Family and twin studies allow for the estimation of the heritability--the influence of genetic factors on the specific phenotype--of the anorexia nervosa in 50-80%. Due to the low prevalence of the disease, the adoption studies have not been performed. The rapid development of the molecular biology methods gives possibility for the searching of the specific genes increasing the risk of anorexia nervosa. Linkage studies are based on scanning the whole genome for loci associated with susceptibility to a certain disease. In the preliminary studies, no linkage was found between anorexia nervosa and the markers on the chromosomes 1-5, 13 and X. In the association studies, relationship between vulnerability to AN and polymorphism in 5-HT2a receptor and uncoupling proteins gene were reported. These results need further confirmation.

[Detection of anti-Borna disease virus antibodies in patients hospitalized in psychiatric hospitals located in the mid-Western region of Poland]. / Przeciwciala prezeciwko wirusowi choroby Borna u pacjentów hospitalizowanych w szpitalach psychiatrycznych na terenach województw lubuskiego i wielkopolskiego.

Borna Disease Virus (BDV) is single stranded RNA virus, which may infect a wide range of animal species. Manifestations of the experimental BDV infection show some resemblance to psychopathological symptoms of mental disorders in humans. Several reports suggest the higher prevalence of anti-BDV antibodies in psychiatric patients than in healthy controls. However, the seroprevalence of anti-BDV antibodies varied due to the different serological methods used in the previous studies. Electrochemiluminescence Immunoassay (ECLIA) is a recently developed, highly specific method of detecting antibodies directed toward two BDV proteins: p24 and p40. We used the ECLIA method for the assessment of seropositivity in 946 psychiatric patients hospitalized in the psychiatric hospitals in the western part of Poland. All patients were clinically diagnosed with ICD-10 criteria. Anti-p40 antibodies have not been found in the studied sample. We found anti p-24 antibodies in 23 cases, which give the seroprevalence rate of 2.4%. This result is consistent with the outcome of Japanese population assessment, done with the same methodology. The seropositive cases did not show diagnostic specificity. We did not find statistically significant gender differences in rate of seropositivity. The seroprevalence of anti-BDV antibodies was not significantly different in patients of urban and rural residence, and in patients of different age groups. This is the first demonstration of anti-BDV antibodies in the Polish population of patients hospitalized in psychiatric hospitals.

Effects of continuous and pulsed 2450-MHz radiation on spontaneous lymphoblastoid transformation of human lymphocytes in vitro.

Normal human lymphocytes were isolated from the peripheral blood of healthy donors. One-ml samples containing (10(6)) cells in chromosome medium 1A were exposed for 5 days to conventional heating or to continuous wave (CW) or pulsed wave (PW) 2450-MHz radiation at non-heating (37 degrees C) and various heating levels (temperature increases of 0.5, 1.0, 1.5, and 2 degrees C). The pulsed exposures involved 1-microsecond pulses at pulse repetition frequencies from 100 to 1,000 pulses per second at the same average SAR levels as the CW exposures. Actual average SARs ranged to 12.3 W/kg. Following termination of the incubation period, spontaneous lymphoblastoid transformation was determined with an image analysis system. The results were compared among each of the experimental conditions and with sham-exposed cultures. At non-heating levels, CW exposure did not affect transformation. At heating levels both conventional and CW heating enhanced transformation to the same extent and correlate with the increases in incubation temperature. PW exposure enhanced transformation at non-heating levels. This finding is significant (P less than .002). At heating levels PW exposure enhanced transformation to a greater extent than did conventional or CW heating. This finding is significant at the .02 level. We conclude that PW 2450-MHz radiation acts differently on the process of lymphoblastoid transformation in vitro compared with CW 2450-MHz radiation at the same average SARs.

An automated dosimetry system for microwave and thermal exposure of biological samples in vitro.

A waveguide exposure system with automated sample temperature measurement is described. This system provides on-line determination of the temperature profile over time of biological samples in vitro. It allows automated computation of the specific absorption rate determined from heating/cooling curves, uses minimally-perturbing thermometry, is biocompatible and can be used for measurements of both microwave and conventional heating.

The development of biomedical approaches and concepts in radiofrequency radiation protection.

The approaches and concepts used in the development of radiofrequency radiation (RFR) protection guidelines evolved over the past quarter of a century. The values of exposure limits (EL) proposed by various groups are converging. Early guides specified ELs in incident power density. Recent ELs are based on considerations of the relationship between bioeffects and the magnitude of the whole body average specific absorption rate (WBA-SAR) and current densities induced in the body. Both these quantities may be considered as dosimetric ones. Thresholds for untoward health effects expressed in terms of these quantities were suggested, and may be considered as basic ELs. It is possible to derive a frequency-dependent relationship between incident RFR fields and WBA-SAR and/or induced current densities in the body. ELs specified for the purpose of determining compliance in terms of electric and magnetic field strengths or equivalent plane-wave power density existing at a point where a person could be present, but measured in the absence of the exposed subject, may be considered as derived working limits. The rationales offered for the recommended ELs indicate that the principal consideration in establishing limits for frequencies of 10 MHz and higher is the prevention of thermal injury, thermal being defined as relatable to heating, i.e. an increase in temperature. At lower frequencies, below 100 kHz or 30 kHz, direct effects on membranes of nerve and muscle cells may be the limiting factor. An additional consideration is the hazard of shock and burns from contact with ungrounded large metal objects that are charged by RFR fields. Recent advances in RFR dosimetry led to concerns that exposure to presently accepted derived ELs may result in large local SARs and induced current densities in certain parts of the body. The present review concludes that further refinements to the basis for RFR should be introduced. Threshold for health hazards should be investigated taking into account both direct and thermal bioeffects of RFR. The dose-thermal effects relationships should be quantified using the concepts of SAR, SA and thermal dosage. Several unresolved questions, such as the biological basis for SAR time-averaging, and the limitation of pulse peak power, are briefly discussed.

Effects of 2.45 GHz microwaves on meiotic chromosomes of male CBA/CAY mice.

Male CBA/CAY mice were exposed daily (6 days a week) for 30 minutes in an environmentally controlled waveguide to continuous 2.45 GHz microwave radiation for 2 weeks at average whole body absorbed dose rates of 0.05, 0.5, 10, and 20 mW/g. Shan exposed animals served as controls. Chain translocations were observed at diakinesis at metaphase I in microwave exposed animals. The yield of translocations increased with exposure, and varied nonlinearly with dose rate. An increase in incidence of univalents was seen after exposure at 10 and 20 mW/g. The findings are interpreted to indicate interference with normal spermatogenesis during the exposure period.

Modulation of mammalian immunity by electromagnetic radiation.

There have been reports that electromagnetic radiation (EMR) alters the function of the immune system; however, these reports are often contradictory. This review reexamines the literature and attempts to evaluate the data on potential mechanisms of interaction of EMR on mammalian immune function. This report concludes that there is no convincing evidence that EMR effects on the human immune system are a health hazard. It was suggested by some authors that long-term EMR exposure may impair immune surveillance, and hypothetically thus facilitate tumor growth. Additional research is needed to prove or disprove this hypothesis. Available data indicate that EMR exposure does not affect the ability of cells of the immune system to respond to a subsequent challenge. However, the time-course and magnitude of the response may be affected by exposure following stimulation. Research to date provided evidence that at least at some frequencies and/or amplitude and pulse modulations, the site of primary interaction of EMR is at the cell membrane. However, it was shown that one specific response, the increase in B complement-receptor positive lymphocytes (Cr+) in the mouse is under genetic control by a single gene localized on chromosome 5. It is suggested that cells of the immune system are a convenient model for further studies on mechanisms of EMR interaction with living systems. Future research should be directed at exploring beneficial medical applications of EMR modulation of immune responses.

Radiofrequency radiation exposure limits in Eastern Europe.

Eastern European standards on radiofrequency radiation (RFR) exposure limits (EL) are reviewed. These standards are mandatory. Additional standards specify requirements for equipment and methods for RFR measurements to determine compliance. The standards are based on USSR ELs with the exception of Poland and Czechoslovakia, where different approaches to exposure limitation were used. According to informal private communications, a new joint recommendation on RFR ELs for all countries belonging to the Council of Mutual Economic Cooperation (COMECON) is being developed. As far as can be judged from recent USSR publications, the new recommendations will establish ELs at levels comparable to those indicated in the international guidelines developed by the International Non-Ionizing Radiation Committee of the International Radiation Protection Association (INIRC/IRPA).