Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate ...genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.
The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have ...only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550,000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 x 10(-8), experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.
Background
The first classification of angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance.
...Methods
In total, 1725 consecutive patients with angioedema without wheals were examined at our centre between 1993 and 2012. We excluded from the analysis 667 patients because of incomplete data or because angioedema was related to a specific factor.
Results
According to the new classification of angioedema, the 1058 patients included in this analysis were diagnosed with hereditary (HAE; n = 377) or acquired angioedema (AAE; n = 681). The former group included HAE with C1‐inhibitor (C1‐INH) deficiency (C1‐INH‐HAE; n = 353) and HAE with normal C1‐INH levels (n = 24), of which six had a factor XII mutation (FXII‐HAE) and 18 had disease of unknown origin (U‐HAE). The AAE group included disease with C1‐INH deficiency (C1‐INH‐AAE; n = 49), AAE related to angiotensin‐converting enzyme inhibitor treatment (n = 183), idiopathic histaminergic (IH‐AAE; n = 379) and idiopathic nonhistaminergic angioedema (InH‐AAE; n = 70). We compared hereditary and AAE with uncertain aetiopathogenesis: the FXII‐HAE and U‐HAE groups pooled (FXII/U‐HAE) versus InH‐AAE. The median age at onset of FXII/U‐HAE and InH‐AAE was 26 and 38 years, respectively. In addition, 56% of patients with FXII/U‐HAE and 81% of those with InH‐AAE reported more than five attacks per year (median duration of 48 h). The location of angioedema in patients with FXII/U‐HAE versus those with InH‐AAE was the following: face, 70% versus 86%; tongue, oral cavity or larynx, 55% versus 68%; limbs, 70% versus 56%; and gastrointestinal mucosa, 50% versus 20%. Prophylaxis with tranexamic acid was effective in all six patients with U‐HAE and in 37 of 38 with InH‐AAE who were started on this treatment.
Conclusion
Our findings in this cohort of patients with angioedema provide new information on the clinical characteristics, diagnosis and treatment of this disease.
Misfit strains arising from a film–substrate mismatch can induce novel phases and properties in the epitaxial films of perovskite oxides. Here we employ yet another effect, namely, strain-assisted ...formation of oxygen vacancies. We demonstrate the misfit-promoted presence of oxygen vacancies and related substitutional incorporation of anion dopants in the epitaxial films of archetypal perovskite oxide SrTiO 3 . Both the oxygen vacancies and hydrogen or nitrogen dopants are introduced in situ during the pulsed-laser deposition of the films using compressive substrates. The films exhibit peculiar chemical expansion and optical properties, which are consistent with substitutional anion doping.
Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of ...schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.
Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study ...(GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340 kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P=0.05; odds ratio (OR)=1.24) and German (P=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (P=3 x 10(-6); OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P=0.0001; OR=1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P=1.7 x 10(-5); OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker x marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better ...predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
The cost of genome-wide association (GWA) studies can be prohibitively high when large samples are genotyped. We conducted a GWA study on schizophrenia (SZ) and to reduce the cost, we used DNA ...pooling. We used a parent-offspring trios design to avoid the potential problems of population stratification. We constructed pools from 605 unaffected controls, 574 SZ patients and a third pool from all the parents of the patients. We hybridized each pool eight times on Illumina HumanHap550 arrays. We estimated the allele frequencies of each pool from the averaged intensities of the arrays. The significance level of results in the trios sample was estimated on the basis of the allele frequencies in cases and non-transmitted pseudocontrols, taking into account the technical variability of the data. We selected the highest ranked SNPs for individual genotyping, after excluding poorly performing SNPs and those that showed a trend in the opposite direction in the control pool. We genotyped 63 SNPs in 574 trios and analysed the results with the transmission disequilibrium test. Forty of those were significant at P<0.05, with the best result at P=1.2 x 10(-6) for rs11064768. This SNP is within the gene CCDC60, a coiled-coil domain gene. The third best SNP (P=0.00016) is rs893703, within RBP1, a candidate gene for schizophrenia.
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