Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Virus variant-specific clinical performance of SARS coronavirus two rapid antigen tests in point-of-care use, from November 2020 to January 2022.

OBJECTIVES: Antigen rapid diagnostic tests (RDTs) for SARS coronavirus 2 (SARS-CoV-2) are quick, widely available, and inexpensive. Consequently, RDTs have been established as an alternative and additional diagnostic strategy to quantitative reverse transcription polymerase chain reaction (RT-qPCR). However, reliable clinical and large-scale performance data specific to a SARS-CoV-2 virus variant of concern (VOC) are limited, especially for the Omicron VOC. The aim of this study was to compare RDT performance among different VOCs. METHODS: This single-centre prospective performance assessment compared RDTs from three manufacturers (NADAL, Panbio, MEDsan) with RT-qPCR including deduced standardized viral load from oropharyngeal swabs for detection of SARS-CoV-2 in a clinical point-of-care setting from November 2020 to January 2022. RESULTS: Among 35 479 RDT/RT-qPCR tandems taken from 26 940 individuals, 164 of the 426 SARS-CoV-2 positive samples tested true positive with an RDT corresponding to an RDT sensitivity of 38.50% (95% CI, 34.00-43.20%), with an overall specificity of 99.67% (95% CI, 99.60-99.72%). RDT sensitivity depended on viral load, with decreasing sensitivity accompanied by descending viral load. VOC-dependent sensitivity assessment showed a sensitivity of 42.86% (95% CI, 32.82-53.52%) for the wild-type SARS-CoV-2, 43.42% (95% CI, 32.86-54.61%) for the Alpha VOC, 37.67% (95% CI, 30.22-45.75%) for the Delta VOC, and 33.67% (95% CI, 25.09-43.49%) for the Omicron VOC. Sensitivity in samples with high viral loads of ≥106 SARS-CoV-2 RNA copies per mL was significantly lower in the Omicron VOC (50.00%; 95% CI, 36.12-63.88%) than in the wild-type SARS-CoV-2 (79.31%; 95% CI, 61.61-90.15%; p 0.015). DISCUSSION: RDT sensitivity for detection of the Omicron VOC is reduced in individuals infected with a high viral load, which curtails the effectiveness of RDTs. This aspect furthert: limits the use of RDTs, although RDTs are still an irreplaceable diagnostic tool for rapid, economic point-of-care and extensive SARS-CoV-2 screening.

Clinical performance evaluation of SARS-CoV-2 rapid antigen testing in point of care usage in comparison to RT-qPCR.

BACKGROUND: Antigen rapid diagnostic tests (RDT) for SARS-CoV-2 are fast, broadly available, and inexpensive. Despite this, reliable clinical performance data from large field studies is sparse. METHODS: In a prospective performance evaluation study, RDT from three manufacturers (NADAL®, Panbio™, MEDsan®, conducted on different samples) were compared to quantitative reverse transcription polymerase chain reaction (RT-qPCR) in 5 068 oropharyngeal swabs for detection of SARS-CoV-2 in a hospital setting. Viral load was derived from standardised RT-qPCR Cycle threshold (Ct) values. The data collection period ranged from November 12, 2020 to February 28, 2021. FINDINGS: The sensitivity of RDT compared to RT-qPCR was 42·57% (95% CI 33·38%-52·31%). The specificity was 99·68% (95% CI 99·48%-99·80%). Sensitivity declined with decreasing viral load from 100% in samples with a deduced viral load of ≥108 SARS-CoV-2 RNA copies per ml to 8·82% in samples with a viral load lower than 104 SARS-CoV-2 RNA copies per ml. No significant differences in sensitivity or specificity could be observed between samples with and without spike protein variant B.1.1.7. The NPV in the study cohort was 98·84%; the PPV in persons with typical COVID-19 symptoms was 97·37%, and 28·57% in persons without or with atypical symptoms. INTERPRETATION: RDT are a reliable method to diagnose SARS-CoV-2 infection in persons with high viral load. RDT are a valuable addition to RT-qPCR testing, as they reliably detect infectious persons with high viral loads before RT-qPCR results are available. FUNDING: German Federal Ministry for Education and Science (BMBF), Free State of Bavaria.

Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age.

BACKGROUND: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified. AIMS: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval. METHODS: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al. RESULTS: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ßstd = 0.176, p < 0.001) and age (ßstd = 0.139, p < 0.001) with the QTc interval corrected according to Fridericia's formula. Sex showed a nominal trend towards significance (ßstd = 0.064, p = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis (n = 588) showed a significant association of potassium serum concentrations with the QTc interval (ßstd = -0.104, p = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis (n = 26, ßstd = 0.101, p = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association. CONCLUSIONS: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.

Use of Complementary and Alternative Medicine in Patients with Primary Immunodeficiency: a Multicentric Analysis of 101 Patients.

The term complementary and alternative medicine (CAM) describes a broad spectrum of health care practices that are not an integral part of the conventional health care system. Many patients worldwide use CAM on their own initiative, often in combination with their conventional medical therapy. CAM use is attractive especially to patients with primary immunodeficiency, since they suffer from frequent infections and autoimmunity. Those are frequently addressed by CAM providers. The aim of this multicentric study was to collect information on the use of CAM by these patients and to define characteristics that are associated with the use of CAM. A total of 101 patients with primary immunodeficiencies at German hospitals were surveyed on their CAM use (further 14 patients rejected to participate). Multiple psychological tests (MARS-D, WHO-5, PHQ9, EFQ) were conducted to investigate variations among personality traits associated with CAM use. Additionally, clinical and sociodemographic patient data was collected. A total of 72% of patients used CAM to treat their primary immunodeficiency. The three most frequently used methods were physical exercise or fitness training (65%), dietary supplements (58%), and homeopathy (49%). Most patients did not discuss CAM use with their doctors, mostly because they felt that there was no time for it. CAM plays an important role for patients with primary immunodeficiency in a high-resource health care setting such as Germany. In clinical practice, doctors should create a platform to discuss needs that go beyond conventional therapy.

Wernicke-Kleist-Leonhard phenotypes of endogenous psychoses: a review of their validity
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While the ICD-DSM paradigm has been a major advance in clinical psychiatry, its usefulness for biological psychiatry is debated. By defining consensus-based disorders rather than empirically driven phenotypes, consensus classifications were not an implementation of the biomedical paradigm. In the field of endogenous psychoses, the Wernicke-Kleist-Leonhard (WKL) pathway has optimized the descriptions of 35 major phenotypes using common medical heuristics on lifelong diachronic observations. Regarding their construct validity, WKL phenotypes have good reliability and predictive and face validity. WKL phenotypes come with remarkable evidence for differential validity on age of onset, familiality, pregnancy complications, precipitating factors, and treatment response. Most impressive is the replicated separation of high- and low-familiality phenotypes. Created in the purest tradition of the biomedical paradigm, the WKL phenotypes deserve to be contrasted as credible alternatives with other approaches currently under discussion.
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De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia.

Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part II: Cognition, neuroimaging and genetics.

OBJECTIVES: Schizophrenia is a group of severe psychiatric disorders with high heritability but only low odds ratios of risk genes. Despite progress in the identification of pathophysiological processes, valid biomarkers of the disease are still lacking. METHODS: This comprehensive review summarises recent efforts to identify genetic underpinnings, clinical and cognitive endophenotypes and symptom dimensions of schizophrenia and presents findings from neuroimaging studies with structural, functional and spectroscopy magnetic resonance imaging and positron emission tomography. The potential of findings to be biomarkers of schizophrenia is discussed. RESULTS: Recent findings have not resulted in clear biomarkers for schizophrenia. However, we identified several biomarkers that are potential candidates for future research. Among them, copy number variations and links between genetic polymorphisms derived from genome-wide analysis studies, clinical or cognitive phenotypes, multimodal neuroimaging findings including positron emission tomography and magnetic resonance imaging, and the application of multivariate pattern analyses are promising. CONCLUSIONS: Future studies should address the effects of treatment and stage of the disease more precisely and apply combinations of biomarker candidates. Although biomarkers for schizophrenia await validation, knowledge on candidate genomic and neuroimaging biomarkers is growing rapidly and research on this topic has the potential to identify psychiatric endophenotypes and in the future increase insight on individual treatment response in schizophrenia.

The role of Pannexin gene variants in schizophrenia: systematic analysis of phenotypes.

Pannexins are a group of brain-expressed channel proteins thought to be regulators of schizophrenia-linked pathways including glutamate release, synaptic plasticity and neural stem proliferation. We got evidence for linkage of a catatonic phenotype to the PANX2 locus in a family study. Aim of our study was to evaluate the role of Pannexins in schizophrenia and clinical phenotypes, particularly with regard to periodic catatonia. We genotyped six single-nucleotide polymorphisms at PANX1, five at PANX2 and three at PANX3 in 1173 German cases with schizophrenia according to DSM-5 and 480 controls. Our sample included 338 cases with periodic catatonia corresponding to Leonhard's classification. Association with schizophrenia according to DSM-5 was limited to genotype rs4838858-TT [p = 0.02, odds ratio (OR) 3.1] and haplotype rs4838858T-rs5771206G (p = 0.02, OR 2.7) at PANX2. We found no significant association with clinical phenotypes. Our limited findings do not support a major contribution of PANX1-3 to disease risk of schizophrenia according to DSM-5. We cannot confirm an association of the PANX2 loci at chromosome 22q13 with periodic catatonia.

Is Ankyrin a genetic risk factor for psychiatric phenotypes?

BACKGROUND: Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. METHODS: We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. RESULTS: We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. CONCLUSION: Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.

The DAOA/G30 locus and affective disorders: haplotype based association study in a polydiagnostic approach.

BACKGROUND: The DAOA/G30 (D-amino acid oxidase activator) gene complex at chromosomal region 13q32-33 is one of the most intriguing susceptibility loci for the major psychiatric disorders, although there is no consensus about the specific risk alleles or haplotypes across studies. METHODS: In a case-control sample of German descent (affective psychosis: n = 248; controls: n = 188) we examined seven single nucleotide polymorphisms (SNPs) around DAOA/G30 (rs3916966, rs1935058, rs2391191, rs1935062, rs947267, rs3918342, and rs9558575) for genetic association in a polydiagnostic approach (ICD 10; Leonhard's classification). RESULTS: No single marker showed evidence of overall association with affective disorder neither in ICD10 nor Leonhard's classification. Haplotype analysis revealed no association with recurrent unipolar depression or bipolar disorder according to ICD10, within Leonhard's classification manic-depression was associated with a 3-locus haplotype (rs2391191, rs1935062, and rs3916966; P = 0.022) and monopolar depression with a 5-locus combination at the DAOA/G30 core region (P = 0.036). CONCLUSION: Our data revealed potential evidence for partially overlapping risk haplotypes at the DAOA/G30 locus in Leonhard's affective psychoses, but do not support a common genetic contribution of the DAOA/G30 gene complex to the pathogenesis of affective disorders.

Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers.

Objective. The phenotypic complexity, together with the multifarious nature of the so-called "schizophrenic psychoses", limits our ability to form a simple and logical biologically based hypothesis for the disease group. Biological markers are defined as biochemical, physiological or anatomical traits that are specific to particular conditions. An important aim of biomarker discovery is the detection of disease correlates that can be used as diagnostic tools. Method. A selective review of the WFSBP Task Force on Biological Markers in schizophrenia is provided from the central nervous system to phenotypes, functional brain systems, chromosomal loci with potential genetic markers to the peripheral systems. Results. A number of biological measures have been proposed to be correlated with schizophrenia. At present, not a single biological trait in schizophrenia is available which achieves sufficient specificity, selectivity and is based on causal pathology and predictive validity to be recommended as diagnostic marker. Conclusions. With the emergence of new technologies and rigorous phenotypic subclassification the identification of genetic bases and assessment of dynamic disease related alterations will hopefully come to a new stage in the complex field of psychiatric research.

GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) and haplotypes in intron 8 of type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were initially found to be associated with schizophrenia in Chinese. This finding was subjected to cross-validation in this study with Japanese (JP) and German Caucasian (GE) subjects. METHODS: Single nucleotide polymorphisms discovery and genotyping were carried out through resequencing of a 1839 base pair (bp) region in GABRB2. Tagging SNPs (tSNPs) were selected based on linkage disequilibrium (LD), combinations of which were analyzed with Bonferroni correction and permutation for disease association. Random resampling was applied to generate size- and gender-balanced cases and control subjects. RESULTS: Out of the 17 SNPs (9.2/kilobase [kb]) revealed, 6 were population-specific. Population variations in LD were observable, and at least two low LD points were identified in both populations. Although disease association at single SNP level was only shown in GE, strong association was demonstrated in both JP (p = .0002 - .0191) and GE (p = .0033 - .0410) subjects, centering on haplotypes containing rs1816072 and rs1816071. Among different clinical subtypes, the most significant association was exhibited by systematic schizophrenia. CONCLUSIONS: Cross-population validation of GABRB2 association with schizophrenia has been obtained with JP and GE subjects, with the genotype-disease correlations being strongest in systematic schizophrenia, the most severe subtype of the disease.

Is FKBP5 a genetic marker of affective psychosis? A case control study and analysis of disease related traits.

BACKGROUND: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important pathogenic factor in depression. Genetic variants of FKBP5, a protein of the HPA system modulating the glucocorticoid receptor, have been reported to be genetically associated with improved response to medical treatment and an increase of depressive episodes. METHODS: We examined three single nucleotide polymorphisms (SNPs) in FKBP5, rs4713916 in the proposed promoter region, rs1360780 in the second intron and rs3800373 in the 3'-untranslated region (3'-UTR), in a case-control study of Caucasian origin (affective psychosis: n = 248; controls: n = 188) for genetic association and association with disease related traits. RESULTS: Allele and genotype frequencies of rs4713916, rs1360780 and rs3800373 were not significantly different between cases and controls. Two three-locus haplotypes, G-C-T and A-T-G, accounted for 86.2% in controls. Odds ratios were not increased between cases and controls, except the rare haplotype G-C-G (OR 6.81), representing 2.1% of cases and 0.3% of controls. The frequency of rs4713916AG in patients deviated from expected Hardy-Weinberg equilibrium, the genotype AA at rs4713916 in monopolar depression (P = 0.011), and the two-locus haplotype rs1360780T--rs3800373T in the total sample (overall P = 0.045) were nominally associated with longer continuance of disease. CONCLUSION: Our data do not support a significant genetic contribution of FKBP5 polymorphisms and haplotypes to affective psychosis, and the findings are inconclusive regarding their contribution to disease-related traits.

ZDHHC8 as a candidate gene for schizophrenia: analysis of a putative functional intronic marker in case-control and family-based association studies.

BACKGROUND: The chromosome 22q11 region is proposed as a major candidate locus for susceptibility genes to schizophrenia. Recently, the gene ZDHHC8 encoding a putative palmitoyltransferase at 22q11 was proposed to increase liability to schizophrenia based on both animal models and human association studies by significant over-transmission of allele rs175174A in female, but not male subjects with schizophrenia. METHODS: Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we examined rs175174 in 204 German proband-parent triads and in an independent case-control study (schizophrenic cases: n = 433; controls: n = 186). RESULTS: In the triads heterozygous parents transmitted allele G preferentially to females, and allele A to males (heterogeneity chi2 = 4.43; p = 0.035). The case-control sample provided no further evidence for overall or gender-specific effects regarding allele and genotype frequency distributions. CONCLUSION: The findings on rs175174 at ZDHHC8 are still far from being conclusive, but evidence for sexual dimorphism is moderate, and our data do not support a significant genetic contribution of rs175174 to the aetiopathogenesis of schizophrenia.

Systematic mutation analysis of KIAA0767 and KIAA1646 in chromosome 22q-linked periodic catatonia.

BACKGROUND: Periodic catatonia is a familial subtype of schizophrenia characterized by hyperkinetic and akinetic episodes, followed by a catatonic residual syndrome. The phenotype has been evaluated in two independent genome-wide linkage scans with evidence for a major locus on chromosome 15q15, and a second independent locus on chromosome 22qtel. METHODS: In the positional and brain-expressed candidate genes KIAA0767 and KIAA1646, we searched for variants in the complete exons and adjacent splice-junctions as well as in parts of the 5'- and 3'-untranslated regions by means of a systematic mutation screening in individuals from chromosome 22q-linked pedigrees. RESULTS: The mutation scan revealed 24 single nucleotide polymorphisms, among them two rare codon variants (KIAA0767: S159I; KIAA1646: V338G). However, both were neither found segregating with the disease in the respective pedigree nor found at a significant frequency in a case-control association sample. CONCLUSION: Starting from linkage signals at chromosome22qtel in periodic catatonia, we screened two positional brain-expressed candidate genes for genetic variation. Our study excludes genetic variations in the coding and putative promoter regions of KIAA0767 and KIAA1646 as causative factors for periodic catatonia.