Prevalence of autoimmune diseases in functional neurological disorder: influence of psychiatric comorbidities and biological sex.

BACKGROUND: Functional neurological disorder (FND) is a common and disabling neuropsychiatric condition, which disproportionally affects women compared with men. While the etiopathogenesis of this disorder remains elusive, immune dysregulation is emerging as one potential mechanism. To begin to understand the role of immune dysfunctions in FND, we assessed the prevalence of several common autoimmune diseases (ADs) in a large cohort of patients with FND and examined the influence of psychiatric comorbidities and biological sex. METHODS: Using a large biorepository database (Mass General Brigham Biobank), we obtained demographic and clinical data of a cohort of 643 patients diagnosed with FND between January 2015 and December 2021. The proportion of ADs was calculated overall, by sex and by the presence of psychiatric comorbidities. RESULTS: The overall prevalence of ADs in our sample was 41.9%, with connective tissue and autoimmune endocrine diseases being the most commonly observed ADs. Among patients with FND and ADs, 27.7% had ≥2 ADs and 8% met criteria for multiple autoimmune syndrome. Rates of ADs were significantly higher in subjects with comorbid major depressive disorder and post-traumatic stress disorder (p= 0.02). Women represented the largest proportion of patients with concurrent ADs, both in the overall sample and in the subgroups of interest (p's < 0.05). CONCLUSIONS: This study is unique in providing evidence of an association between FND and ADs. Future studies are needed to investigate the mechanisms underlying this association and to understand whether FND is characterised by distinct dysregulations in immune response.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

A genetic association study of CSMD1 and CSMD2 with cognitive function.

The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n=670). Replication testing of SNPs with p-value<0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n=1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n=1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMD1 SNP rs2740931 and performance in immediate episodic memory (p-value=5×10-6, minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p⩽1.2×10-5). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n=3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease.

Linkage-disequilibrium-based binning affects the interpretation of GWASs.

Genome-wide association studies (GWASs) are critically dependent on detailed knowledge of the pattern of linkage disequilibrium (LD) in the human genome. GWASs generate lists of variants, usually SNPs, ranked according to the significance of their association to a trait. Downstream analyses generally focus on the gene or genes that are physically closest to these SNPs and ignore their LD profile with other SNPs. We have developed a flexible R package (LDsnpR) that efficiently assigns SNPs to genes on the basis of both their physical position and their pairwise LD with other SNPs. We used the positional-binning and LD-based-binning approaches to investigate whether including these "LD-based" SNPs would affect the interpretation of three published GWASs on bipolar affective disorder (BP) and of the imputed versions of two of these GWASs. We show how including LD can be important for interpreting and comparing GWASs. In the published, unimputed GWASs, LD-based binning effectively "recovered" 6.1%-8.3% of Ensembl-defined genes. It altered the ranks of the genes and resulted in nonnegligible differences between the lists of the top 2,000 genes emerging from the two binning approaches. It also improved the overall gene-based concordance between independent BP studies. In the imputed datasets, although the increases in coverage (>0.4%) and rank changes were more modest, even greater concordance between the studies was observed, attesting to the potential of LD-based binning on imputed data as well. Thus, ignoring LD can result in the misinterpretation of the GWAS findings and have an impact on subsequent genetic and functional studies.

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.

SUMO modification is required for in vivo Hox gene regulation by the Caenorhabditis elegans Polycomb group protein SOP-2.

Post-translational modification of proteins by the ubiquitin-like molecule SUMO (sumoylation) regulates their subcellular localization and affects their functional properties in vitro, but the physiological function of sumoylation in multicellular organisms is largely unknown. Here, we show that the C. elegans Polycomb group (PcG) protein SOP-2 interacts with the SUMO-conjugating enzyme UBC-9 through its evolutionarily conserved SAM domain. Sumoylation of SOP-2 is required for its localization to nuclear bodies in vivo and for its physiological repression of Hox genes. Global disruption of sumoylation phenocopies a sop-2 mutation by causing ectopic Hox gene expression and homeotic transformations. Chimeric constructs in which the SOP-2 SAM domain is replaced with that derived from fruit fly or mammalian PcG proteins, but not those in which the SOP-2 SAM domain is replaced with the SAM domains of non-PcG proteins, confer appropriate in vivo nuclear localization and Hox gene repression. These observations indicate that sumoylation of PcG proteins, modulated by their evolutionarily conserved SAM domain, is essential to their physiological repression of Hox genes.

Imaging and cognitive genetics: the Norwegian Cognitive NeuroGenetics sample.

Data collection for the Norwegian Cognitive NeuroGenetics sample (NCNG) was initiated in 2003 with a research grant (to Ivar Reinvang) to study cognitive aging, brain function, and genetic risk factors. The original focus was on the effects of aging (from middle age and up) and candidate genes (e.g., APOE, CHRNA4) in cross-sectional and longitudinal designs, with the cognitive and MRI-based data primarily being used for this purpose. However, as the main topic of the project broadened from cognitive aging to imaging and cognitive genetics more generally, the sample size, age range of the participants, and scope of available phenotypes and genotypes, have developed beyond the initial project. In 2009, a genome-wide association (GWA) study was undertaken, and the NCNG proper was established to study the genetics of cognitive and brain function more comprehensively. The NCNG is now controlled by the NCNG Study Group, which consists of the present authors. Prominent features of the NCNG are the adult life-span coverage of healthy participants with high-dimensional imaging, and cognitive data from a genetically homogenous sample. Another unique property is the large-scale (sample size 300-700) use of experimental cognitive tasks focusing on attention and working memory. The NCNG data is now used in numerous ongoing GWA-based studies and has contributed to several international consortia on imaging and cognitive genetics. The objective of the following presentation is to give other researchers the information necessary to evaluate possible contributions from the NCNG to various multi-sample data analyses.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Which behaviours are first to emerge during recovery of consciousness after severe brain injury?

BACKGROUND: Early detection of consciousness after severe brain injury is critical for establishing an accurate prognosis and planning appropriate treatment. OBJECTIVES: To determine which behavioural signs of consciousness emerge first and to estimate the time course to recovery of consciousness in patients with severe acquired brain injury. METHODS: Retrospective observational study using the Coma Recovery Scale-Revised and days to recovery of consciousness in 79 patients (51 males; 34 with traumatic brain injury; median [IQR] age 48 [26-61] years; median time since injury 26 [20-36] days) who transitioned from coma or unresponsive wakefulness syndrome (UWS)/vegetative state (VS) to the minimally conscious state (MCS) or emerged from MCS during inpatient rehabilitation. RESULTS: Visual pursuit was the most common initial sign of MCS (41% of patients; 95% CI [30-52]), followed by reproducible command-following (25% [16-35]) and automatic movements (24% [15-33]). Ten other behaviours emerged first in less than 16% of cases. Median [IQR] time to recovery of consciousness was 44 [33-59] days. Etiology did not significantly affect time to recovered consciousness. CONCLUSION: Recovery of consciousness after severe brain injury is most often signalled by reemergence of visual pursuit, reproducible command-following and automatic movements. Clinicians should use assessment measures that are sensitive to these behaviours because early detection of consciousness is critical for accurate prognostication and treatment planning.

Behavioral Recovery and Early Decision Making in Patients with Prolonged Disturbance in Consciousness after Traumatic Brain Injury.

The extent of behavioral recovery that occurs in patients with traumatic disorders of consciousness (DoC) following discharge from the acute care setting has been under-studied and increases the risk of overly pessimistic outcome prediction. The aim of this observational cohort study was to systematically track behavioral and functional recovery in patients with prolonged traumatic DoC following discharge from the acute care setting. Standardized behavioral data were acquired from 95 patients in a minimally conscious (MCS) or vegetative state (VS) recruited from 11 clinic sites and randomly assigned to the placebo arm of a previously completed prospective clinical trial. Patients were followed for 6 weeks by blinded observers to determine frequency of recovery of six target behaviors associated with functional status. The Coma Recovery Scale-Revised and Disability Rating Scale were used to track reemergence of target behaviors and assess degree of functional disability, respectively. Twenty percent (95% confidence interval [CI]: 13-30%) of participants (mean age 37.2; median 47 days post-injury; 69 men) recovered all six target behaviors within the 6 week observation period. The odds of recovering a specific target behavior were 3.2 (95% CI: 1.2-8.1) to 7.8 (95% CI: 2.7-23.0) times higher for patients in MCS than for those in VS. Patients with preserved language function ("MCS+") recovered the most behaviors (p ≤ 0.002) and had the least disability (p ≤ 0.002) at follow-up. These findings suggest that recovery of high-level behaviors underpinning functional independence is common in patients with prolonged traumatic DoC. Clinicians involved in early prognostic counseling should recognize that failure to emerge from traumatic DoC before 28 days does not necessarily portend unfavorable outcome.

An evidence-based methodology for systematic evaluation of clinical outcome assessment measures for traumatic brain injury.

INTRODUCTION: The high failure rate of clinical trials in traumatic brain injury (TBI) may be attributable, in part, to the use of untested or insensitive measurement instruments. Of more than 1,000 clinical outcome assessment measures (COAs) for TBI, few have been systematically vetted to determine their performance within specific "contexts of use (COU)." As described in guidance issued by the U.S. Food and Drug Administration (FDA), the COU specifies the population of interest and the purpose for which the COA will be employed. COAs are commonly used for screening, diagnostic categorization, outcome prediction, and establishing treatment effectiveness. COA selection typically relies on expert consensus; there is no established methodology to match the appropriateness of a particular COA to a specific COU. We developed and pilot-tested the Evidence-Based Clinical Outcome assessment Platform (EB-COP) to systematically and transparently evaluate the suitability of TBI COAs for specific purposes. METHODS AND FINDINGS: Following a review of existing literature and published guidelines on psychometric standards for COAs, we developed a 6-step, semi-automated, evidence-based assessment platform to grade COA performance for six specific purposes: diagnosis, symptom detection, prognosis, natural history, subgroup stratification and treatment effectiveness. Mandatory quality indicators (QIs) were identified for each purpose using a modified Delphi consensus-building process. The EB-COP framework was incorporated into a Qualtrics software platform and pilot-tested on the Glasgow Outcome Scale-Extended (GOSE), the most widely-used COA in TBI clinical studies. CONCLUSION: The EB-COP provides a systematic methodology for conducting more precise, evidence-based assessment of COAs by evaluating performance within specific COUs. The EB-COP platform was shown to be feasible when applied to a TBI COA frequently used to detect treatment effects and can be modified to address other populations and COUs. Additional testing and validation of the EB-COP are warranted.

Targeted Metabolomic Profiling Reveals Association Between Altered Amino Acids and Poor Functional Recovery After Stroke.

Amino acids have been shown to be among the most important metabolites to be altered following stroke; however, they are a double-edged sword with regard to regulating hemostasis. In this study, we conducted a targeted metabolomic study to examine the association between serum levels of amino acids and functional recovery after stroke. Three hundred and fifty-one patients with stroke admitted to an acute rehabilitation hospital were screened, and 106 patients were selected based on inclusion and exclusion criteria. Recruited patients were stratified using Montebello Rehabilitation Factor Score (MRFS) efficiency. We selected the top (n = 20, 19%) and bottom (n = 20, 19%) of MRFS efficiency for metabolomic analysis. A total of 21 serum amino acids levels were measured using ultra high performance liquid chromatography and mass spectrometry. The normalized data were analyzed by multivariate approaches, and the selected potential biomarkers were combined in different combinations for prediction of stroke functional recovery. The results demonstrated that there were significant differences in leucine-isoleucine, proline, threonine, glutamic acid, and arginine levels between good and poor recovery groups. In the training (0.952) and test (0.835) sets, metabolite biomarker panels composed of proline, glutamic acid, and arginine had the highest sensitivity and specificity in distinguishing good recovery from poor. In particular, arginine was present in the top 10 combinations of the average area under the receiver operating characteristic curve (AUC) test set. Our findings suggest that amino acids related to energy metabolism and excitotoxicity may play an important role in functional recovery after stroke. Therefore, the level of serum arginine has predictive value for the recovery rate after stroke.

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Short-term effectiveness of a community-implemented falls prevention referral service.

PURPOSE: To evaluate the effectiveness of the 16-week evidence-based Steady Steps exercise referral scheme at improving physical function, balance confidence, and quality of life (QoL) of community-dwelling older adults at risk of falling. METHOD: A non-experimental, practice-based study involving a retrospective analysis of participant outcomes. Pre-post comparisons of three performance-based measures of gait and balance and of person-reported outcomes for balance confidence and QoL were performed. Effectiveness was evaluated in terms of statistically significant changes and relative to published fall-risk thresholds and minimal detectable changes (MDCs) or minimum clinically important differences. RESULTS: One hundred and thirty-six participants completed the program over 19 months. Statistically significant differences were observed for all outcomes (p < 0.001), translating to an overall 42.6% reduction in falls-related risk. Approximately 63% of participants achieved an improvement ≥MDC in at least one of the performance-based tests. Greater than 55% achieved self-reported improvements in balance confidence ≥ MDC, while >40% reported clinically important improvements in QoL. CONCLUSIONS: While the non-experimental design precludes conclusive evidence of causation, the highly significant and clinically meaningful improvements observed in individuals who completed the evidence-based Steady Steps program support its translation of evidence into effective practice. Continued implementation and evaluation of such practices and their longer-term effects are warranted. Implications for Rehabilitation Falls in older adults represent an escalating public health problem, and rehabilitation professionals are charged with developing and/or identifying feasible and effective evidence-based programs that target and reduce falls risk in this population. Our findings support Steady Steps as an effective third-sector referral rehabilitation service that successfully translates research evidence-based exercise interventions into effective practice, positively impacting physical function, balance confidence and quality of life (QoL) in community-dwelling older adults. Our study provides practice-based evidence of the effectiveness of exercise interventions that are progressively challenging, deliver a high dose of moderate to high intensity and target the main falls risk factors of muscle weakness and gait and balance impairment. In spite of their limitations, non-experimental, practice-based approaches provide rehabilitation professionals with feasible opportunities for evaluating existing services, such as Steady Steps, and contributing to the overall evidence-base for falls prevention and management.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Haplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder.

BACKGROUND: Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. METHODS: We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. RESULTS: We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. CONCLUSIONS: Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.

The PDE4B gene confers sex-specific protection against schizophrenia.

BACKGROUND: Phosphodiesterase 4B (PDE4B) is a candidate gene for schizophrenia and affective disorders through its disruption by a chromosomal translocation in an individual with schizophrenia, its inhibition by the antidepressant rolipram, and its physical interaction with another key candidate, Disrupted in Schizophrenia (DISC1). OBJECTIVE: To determine the contribution made by PDE4B to the population risk of schizophrenia and bipolar disorder by carrying out a case-control association study. METHODS: Twenty-six tagging single nucleotide polymorphisms were selected across the PDE4B gene and genotyped in DNA samples from 386 schizophrenia cases, 368 bipolar disorder cases and 455 controls. MAIN RESULTS: Single single nucleotide polymorphisms and a resulting haplotype conferred a protective effect against schizophrenia in the female population. The haplotype result remained significant after correction for multiple testing (P=0.012). CONCLUSION: The observation that a PDE4B haplotype alters the genetic risk of schizophrenia in the Scottish population complements the known participation of this gene in biological processes associated with mental illness. Further studies are needed to replicate this finding and identify underlying sequence variants.

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.