Screening Human Embryos for Polygenic Traits Has Limited Utility.

The increasing proportion of variance in human complex traits explained by polygenic scores, along with progress in preimplantation genetic diagnosis, suggests the possibility of screening embryos for traits such as height or cognitive ability. However, the expected outcomes of embryo screening are unclear, which undermines discussion of associated ethical concerns. Here, we use theory, simulations, and real data to evaluate the potential gain of embryo screening, defined as the difference in trait value between the top-scoring embryo and the average embryo. The gain increases very slowly with the number of embryos but more rapidly with the variance explained by the score. Given current technology, the average gain due to screening would be ≈2.5 cm for height and ≈2.5 IQ points for cognitive ability. These mean values are accompanied by wide prediction intervals, and indeed, in large nuclear families, the majority of children top-scoring for height are not the tallest.

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

GWAS quality score for evaluating associated regions in GWAS analyses.

MOTIVATION: The number of significantly associated regions reported in genome-wide association studies (GWAS) for polygenic traits typically increases with sample size. A traditional tool for quality control and identification of significant regions has been a visual inspection of how significant and correlated genetic variants cluster within a region. However, while inspecting hundreds of regions, this subjective method can misattribute significance to some loci or neglect others that are significant. RESULTS: The GWAS quality score (GQS) identifies suspicious regions and prevents erroneous interpretations with an objective, quantitative and automated method. The GQS assesses all measured single nucleotide polymorphisms (SNPs) that are linked by inheritance to each other [linkage disequilibrium (LD)] and compares the significance of trait association of each SNP to its LD value for the reported index SNP. A GQS value of 1.0 ascribes a high level of confidence to the entire region and its underlying gene(s), while GQS values <1.0 indicate the need to closely inspect the outliers. We applied the GQS to published and non-published genome-wide summary statistics and report suspicious regions requiring secondary inspection while supporting the majority of reported regions from large-scale published meta-analyses. AVAILABILITY AND IMPLEMENTATION: The GQS code/scripts can be cloned from GitHub (https://github.com/Xswapnil/GQS/). The analyst can use whole-genome summary statistics to estimate GQS for each defined region. We also provide an online tool (http://35.227.18.38/) that gives access to the GQS. The quantitative measure of quality attributes by GQS and its visualization is an objective method that enhances the confidence of each genomic hit. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

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.

RICOPILI: Rapid Imputation for COnsortias PIpeLIne.

SUMMARY: Genome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open-sourced Perl-based pipeline was developed to address the challenges of rapidly processing large-scale multi-cohort GWAS studies including quality control (QC), imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing environments. RICOPILI was created as the Psychiatric Genomics Consortium pipeline for GWAS and adopted by other users. The pipeline features (i) technical and genomic QC in case-control and trio cohorts, (ii) genome-wide phasing and imputation, (iv) association analysis, (v) meta-analysis, (vi) polygenic risk scoring and (vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work. AVAILABILITY AND IMPLEMENTATION: RICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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'.

The Impact of Medication Anticholinergic Burden on Cognitive Performance in People With Schizophrenia.

BACKGROUND: Cognitive deficits are prevalent in people with schizophrenia and associated with functional impairments. In addition to antipsychotics, pharmacotherapy in schizophrenia often includes other psychotropics, and some of these agents possess anticholinergic properties, which may impair cognition. The objective of this study was to explore the association between medication anticholinergic burden and cognition in schizophrenia. METHODS: Seven hundred five individuals with schizophrenia completed a neuropsychological battery comprising Judgment of Line Orientation Test, Wechsler Abbreviated Scale of Intelligence Matrix Reasoning, Continuous Performance Test-Identical Pairs Version, and the Brief Assessment of Cognition in Schizophrenia. Cognitive g and 3 cognitive factor scores that include executive function, memory/fluency, and speed of processing/vigilance, which were derived from a previously published analysis, were entered as cognitive variables. Anticholinergic burden was computed using 2 anticholinergic scales: Anticholinergic Burden Scale and Anticholinergic Drug Scale. Duration and severity of illness, antipsychotic dose, smoking status, age, and sex were included as covariates. RESULTS: Anticholinergic burden was associated with poorer cognitive performance in cognitive g, all 3 cognitive domains and most cognitive tasks in multivariate analyses. The associations were statistically significant, but the effect sizes were small (for Anticholinergic Burden Scale, Cohen f = 0.008; for Anticholinergic Drug Scale, Cohen f = 0.017). CONCLUSIONS: Although our results showed a statistically significant association between medications with anticholinergic properties and cognition in people with schizophrenia, the impact is of doubtful or minimal clinical significance.

Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population.

BACKGROUND: Previous studies have shown that individuals with schizophrenia have a greater risk for psoriasis than a typical person. This suggests that there might be a shared genetic etiology between the 2 conditions. We aimed to characterize the potential shared genetic susceptibility between schizophrenia and psoriasis using genome-wide marker genotype data. METHODS: We obtained genetic data on individuals with psoriasis, schizophrenia and control individuals. We applied a marker-based coheritability estimation procedure, polygenic score analysis, a gene set enrichment test and a least absolute shrinkage and selection operator regression model to estimate the potential shared genetic etiology between the 2 diseases. We validated the results in independent schizophrenia and psoriasis cohorts from Singapore. RESULTS: We included 1139 individuals with psoriasis, 744 with schizophrenia and 1678 controls in our analysis, and we validated the results in independent cohorts, including 441 individuals with psoriasis (and 2420 controls) and 1630 with schizophrenia (and 1860 controls). We estimated that a large fraction of schizophrenia and psoriasis risk could be attributed to common variants (h2SNP = 29% ± 5.0%, p = 2.00 × 10-8), with a coheritability estimate between the traits of 21%. We identified 5 variants within the human leukocyte antigen (HLA) gene region, which were most likely to be associated with both diseases and collectively conferred a significant risk effect (odds ratio of highest risk quartile = 6.03, p < 2.00 × 10-16). We discovered that variants contributing most to the shared heritable component between psoriasis and schizophrenia were enriched in antigen processing and cell endoplasmic reticulum. LIMITATIONS: Our sample size was relatively small. The findings of 5 HLA gene variants were complicated by the complex structure in the HLA region. CONCLUSION: We found evidence for a shared genetic etiology between schizophrenia and psoriasis. The mechanism for this shared genetic basis likely involves immune and calcium signalling pathways.

Body mass index, obesity, and psychopathology in patients with schizophrenia.

A number of studies have reported that patients with schizophrenia have a higher body mass index (BMI) than the general population. Few Asian studies have examined BMI in patients with schizophrenia. The aims of the current study were to evaluate the distribution of BMI and prevalence of obesity in a large sample of Chinese patients with schizophrenia (n = 973) and to examine the sociodemographic and clinical correlates of overweight (BMI ≥ 25 kg/m) and obesity (BMI ≥ 30 kg/m). There was a preponderance of patients who were overweight (58.7%) and obese (73.6%) as compared with control subjects. Regression modeling of clinical and symptom factors in schizophrenia patients revealed that females were almost twice as likely to be obese compared with males and patients with comorbid medical conditions were more likely to be obese compared with those who did not have a comorbid medical condition (odds ratio, 1.6). Those prescribed typical antipsychotic medications were 1.7 times more likely to be obese, whereas individuals prescribed with both typical and atypical antipsychotic medications were 2.2 times more likely to be obese as compared with those prescribed atypical antipsychotics. A significant predictor interaction for obesity was observed between sex and typical antipsychotics, sex and comorbid medical conditions, and years of education and comorbid medical conditions. The higher prevalence of obesity in patients with schizophrenia is a matter of clinical and public health concern; interventions to reduce weight to healthy levels would result in both improved health and quality of life among patients with schizophrenia.

Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics.

Given the increasingly large number of loci discovered by psychiatric GWAS, specification of the key biological pathways underlying these loci has become a priority for the field. We have previously leveraged the pleiotropic genetic relationships between schizophrenia and two cognitive phenotypes (educational attainment and cognitive task performance) to differentiate two subsets of illness-relevant SNPs: (1) those with "concordant" alleles, which are associated with reduced cognitive ability/education and increased schizophrenia risk; and (2) those with "discordant" alleles linked to reduced educational and/or cognitive levels but lower schizophrenia susceptibility. In the present study, we extend our prior work, utilizing larger input GWAS datasets and a more powerful statistical approach to pleiotropic meta-analysis, the Pleiotropic Locus Exploration and Interpretation using Optimal test (PLEIO). Our pleiotropic meta-analysis of schizophrenia and the two cognitive phenotypes revealed 768 significant loci (159 novel). Among these, 347 loci harbored concordant SNPs, 270 encompassed discordant SNPs, and 151 "dual" loci contained concordant and discordant SNPs. Competitive gene-set analysis using MAGMA related concordant SNP loci with neurodevelopmental pathways (e.g., neurogenesis), whereas discordant loci were associated with mature neuronal synaptic functions. These distinctions were also observed in BrainSpan analysis of temporal enrichment patterns across developmental periods, with concordant loci containing more prenatally expressed genes than discordant loci. Dual loci were enriched for genes related to mRNA translation initiation, representing a novel finding in the schizophrenia literature.

Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance.

Background: Research on peripheral (e.g., blood-based) biomarkers for psychiatric illness has typically been low-throughput in terms of both the number of subjects and the range of assays performed. Moreover, traditional case-control studies examining blood-based biomarkers are subject to potential confounds of treatment and other exposures common to patients with psychiatric illnesses. Our research addresses these challenges by leveraging large-scale, high-throughput proteomics data and Mendelian Randomization (MR) to examine the causal impact of circulating proteins on psychiatric phenotypes and cognitive task performance. Methods: We utilized plasma proteomics data from the UK Biobank (3,072 proteins assayed in 34,557 European-ancestry individuals) and deCODE Genetics (4,719 proteins measured across 35,559 Icelandic individuals). Significant proteomic quantitative trait loci (both cis-pQTLs and trans-pQTLs) served as MR instruments, with the most recent GWAS for schizophrenia, bipolar disorder, major depressive disorder, and cognitive task performance (all excluding overlapping UK Biobank participants) as phenotypic outcomes. Results: MR revealed 109 Bonferroni-corrected causal associations (44 novel) involving 88 proteins across the four phenotypes. Several immune-related proteins, including interleukins and complement factors, stood out as pleiotropic across multiple outcome phenotypes. Drug target enrichment analysis identified several novel potential pharmacologic repurposing opportunities, including anti-inflammatory agents for schizophrenia and bipolar disorder and duloxetine for cognitive performance. Conclusions: Identification of causal effects for these circulating proteins suggests potential biomarkers for these conditions and offers insights for developing innovative therapeutic strategies. The findings also indicate substantial evidence for the pleiotropic effects of many proteins across different phenotypes, shedding light on the shared etiology among psychiatric conditions and cognitive ability.

Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression.

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants. We showed that the burden of rare damaging coding variants in loss-of-function intolerant genes is significantly associated with risk of depression with various definitions. We compared the rare and common genetic architecture across depression definitions by genetic correlation and showed different genetic relationships between definitions across common and rare variants. In addition, we demonstrated that the effects of rare damaging coding variant burden and polygenic risk score on depression risk are additive. The gene set burden analyses revealed overlapping rare genetic variant components with developmental disorder, autism, and schizophrenia. Our study provides insights into the contribution of rare coding variants, separately and in conjunction with common variants, on depression with various definitions and their genetic relationships with neurodevelopmental disorders.

Shared genetic architectures of educational attainment in East Asian and European populations.

Educational attainment (EduYears), a heritable trait often used as a proxy for cognitive ability, is associated with various health and social outcomes. Previous genome-wide association studies (GWASs) on EduYears have been focused on samples of European (EUR) genetic ancestries. Here we present the first large-scale GWAS of EduYears in people of East Asian (EAS) ancestry (n = 176,400) and conduct a cross-ancestry meta-analysis with EduYears GWAS in people of EUR ancestry (n = 766,345). EduYears showed a high genetic correlation and power-adjusted transferability ratio between EAS and EUR. We also found similar functional enrichment, gene expression enrichment and cross-trait genetic correlations between two populations. Cross-ancestry fine-mapping identified refined credible sets with a higher posterior inclusion probability than single population fine-mapping. Polygenic prediction analysis in four independent EAS and EUR cohorts demonstrated transferability between populations. Our study supports the need for further research on diverse ancestries to increase our understanding of the genetic basis of educational attainment.

Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Transcriptome-Wide Structural Equation Modeling of 13 Major Psychiatric Disorders for Cross-Disorder Risk and Drug Repurposing.

Importance: Psychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy. Objective: To identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes. Design, Setting, and Participants: This genomic study applied a multivariate transcriptomic method, transcriptome-wide structural equation modeling (T-SEM), to investigate gene expression patterns associated with 5 genomic factors indexing shared risk across 13 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. The Broad Institute Connectivity Map Drug Repurposing Database and Drug-Gene Interaction Database public databases of drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk. Data were collected from database inception up to February 20, 2023. Main Outcomes and Measures: Gene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes. Results: In total, T-SEM identified 466 genes whose expression was significantly associated (z ≥ 5.02) with genomic factors and 36 genes with disorder-specific effects. Most associated genes were found for a thought disorders factor, defined by bipolar disorder and schizophrenia. Several existing pharmacological interventions were identified that could be repurposed to target genes whose expression was associated with the thought disorders factor or a transdiagnostic p factor defined by all 13 disorders. Conclusions and Relevance: The findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.

Deconstructing the genetic architecture of treatment-resistant schizophrenia in East Asian ancestry.

BACKGROUND: Treatment-resistant schizophrenia (TRS) affects a substantial proportion of patients who do not respond adequately to antipsychotic medications, yet the underlying biological mechanism remains poorly understood. This study investigates the link between the genetic predisposition to schizophrenia and TRS. METHODS: 857 individuals diagnosed with schizophrenia were divided into TRS (n = 142) and non-TRS (n = 715) based on well-defined TRS criteria. Polygenic risk scores (PRS) were calculated using schizophrenia genome-wide association summary statistics from East-Asian and European ancestry populations. PRS was estimated using both P-value thresholding and Bayesian framework methods. Logistic regression analyses were performed to differentiate between TRS and non-TRS individuals. RESULTS: The schizophrenia PRS derived from the East-Asian training dataset effectively distinguished between TRS and non-TRS individuals (R2 = 0.029, p = 4.86 ×10-5, pT = 0.1, OR = 1.52, 95% CI = 1.242-1.861), with higher PRS values observed in the TRS group. Similar PRS analysis was conducted based on the European ancestry GWAS summary statistics, but we found superior prediction based on the East-Asian ancestry discovery data. CONCLUSION: This study reveals an association between common risk variants for schizophrenia and TRS status, suggesting that the genetic burden of schizophrenia may partly contribute to treatment resistance in individuals with schizophrenia. These findings propose the potential use of genetic risk factors for early TRS identification and timely access to clozapine. However, the ancestral background of the discovery sample is crucial for successfully implementing PRS in clinical settings.

Genome-wide Association Study Shows That Executive Functioning Is Influenced by GABAergic Processes and Is a Neurocognitive Genetic Correlate of Psychiatric Disorders.

BACKGROUND: Deficits in executive functions (EFs), cognitive processes that control goal-directed behaviors, are associated with psychopathology and neurologic disorders. Little is known about the molecular bases of individual differences in EFs. Prior candidate gene studies have been underpowered in their search for dopaminergic processes involved in cognitive functioning, and existing genome-wide association studies of EFs used small sample sizes and/or focused on individual tasks that are imprecise measures of EFs. METHODS: We conducted a genome-wide association study of a common EF (cEF) factor score based on multiple tasks in the UK Biobank (n = 427,037 individuals of European descent). RESULTS: We found 129 independent genome-wide significant lead variants in 112 distinct loci. cEF was associated with fast synaptic transmission processes (synaptic, potassium channel, and GABA [gamma-aminobutyric acid] pathways) in gene-based analyses. cEF was genetically correlated with measures of intelligence (IQ) and cognitive processing speed, but cEF and IQ showed differential genetic associations with psychiatric disorders and educational attainment. CONCLUSIONS: Results suggest that cEF is a genetically distinct cognitive construct that is particularly relevant to understanding the genetic variance in psychiatric disorders.

The impact of rare protein coding genetic variation on adult cognitive function.

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.