Thyroid function variations within the reference range and cognitive function: A two-sample Mendelian randomization study.

BACKGROUND: The causal relationship between thyroid function variations within the reference range and cognitive function remains unknown. We aimed to explore this causal relationship using a Mendelian randomization (MR) approach. METHODS: Summary statistics of a thyroid function genome-wide association study (GWAS) were obtained from the ThyroidOmics consortium, including reference range thyroid stimulating hormone (TSH) (N = 54,288) and reference range free thyroxine (FT4) (N = 49,269). GWAS summary statistics on cognitive function were obtained from the Social Science Genetic Association Consortium (SSGAC) and the UK Biobank, including cognitive performance (N = 257,841), prospective memory (N = 152,605), reaction time (N = 459,523), and fluid intelligence (N = 149,051). The primary method used was inverse-variance weighted (IVW), supplemented with weighted median, Mr-Egger regression, and MR-Pleiotropy Residual Sum and Outlier. Several sensitivity analyses were conducted to identify heterogeneity and pleiotropy. RESULTS: An increase in genetically associated TSH within the reference range was suggestively associated with a decline in cognitive performance (ß = -0.019; 95%CI: -0.034 to -0.003; P = 0.017) and significantly associated with longer reaction time (ß = 0.016; 95 % CI: 0.005 to 0.027; P = 0.004). Genetically associated FT4 levels within the reference range had a significant negative relationship with reaction time (ß = -0.030; 95%CI:-0.044 to -0.015; P = 4.85 × 10-5). These findings remained robust in the sensitivity analyses. CONCLUSIONS: Low thyroid function within the reference range may have a negative effect on cognitive function, but further research is needed to fully understand the nature of this relationship. LIMITATIONS: This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups.

Gene-environment pathways to cognitive intelligence and psychotic-like experiences in children.

In children, psychotic-like experiences (PLEs) are related to risk of psychosis, schizophrenia, and other mental disorders. Maladaptive cognitive functioning, influenced by genetic and environmental factors, is hypothesized to mediate the relationship between these factors and childhood PLEs. Using large-scale longitudinal data, we tested the relationships of genetic and environmental factors (such as familial and neighborhood environment) with cognitive intelligence and their relationships with current and future PLEs in children. We leveraged large-scale multimodal data of 6,602 children from the Adolescent Brain and Cognitive Development Study. Linear mixed model and a novel structural equation modeling (SEM) method that allows estimation of both components and factors were used to estimate the joint effects of cognitive phenotypes polygenic scores (PGSs), familial and neighborhood socioeconomic status (SES), and supportive environment on NIH Toolbox cognitive intelligence and PLEs. We adjusted for ethnicity (genetically defined), schizophrenia PGS, and additionally unobserved confounders (using computational confound modeling). Our findings indicate that lower cognitive intelligence and higher PLEs are significantly associated with lower PGSs for cognitive phenotypes, lower familial SES, lower neighborhood SES, and less supportive environments. Specifically, cognitive intelligence mediates the effects of these factors on PLEs, with supportive parenting and positive school environments showing the strongest impact on reducing PLEs. This study underscores the influence of genetic and environmental factors on PLEs through their effects on cognitive intelligence. Our findings have policy implications in that improving school and family environments and promoting local economic development may enhance cognitive and mental health in children.

Childhood is a critical period for brain development. Difficult experiences during this developmental phase may contribute to reduced intelligence and poorer mental health later in life. Genetics and environmental factors also play roles. For example, having family support or a higher family income has been linked to better brain health outcomes for children. Delusions or hallucinations, or other psychotic-like experiences during childhood, are linked with poor mental health later in life. Children who experience psychotic-like episodes between the ages of nine and eleven have a higher risk of developing schizophrenia or related conditions. Environmental circumstances during childhood also appear to play a crucial role in shaping the risk of schizophrenia or related conditions. Park, Lee et al. show that positive parenting and supportive school and neighborhood environments boost child intelligence and mental health. In the experiments, Park, Lee et al. analyzed data on 6,602 children to determine how genetics and environmental factors shaped their intelligence and mental health. The models show that children with higher intelligence have a lower risk of psychosis. Both genetics and supportive environments contribute to higher intelligence. Complex interactions between biology and social factors shape children's intelligence and mental health. Beneficial genetics and coming from a family with more financial resources are helpful. Yet, social environments, such as having parents who use positive child-rearing practices, or having supportive schools or neighborhoods, have protective effects that can offset other disadvantages. Policies that help parents, encourage supportive school environments, and strengthen neighborhoods may boost children's intelligence and mental health later in life.

Studying the relationship between intelligence quotient and schizophrenia polygenic scores in a family design with first-episode psychosis population.

BACKGROUND: The intelligence quotient (IQ) of patients with first-episode psychosis (FEP) and their unaffected relatives may be related to the genetic burden of schizophrenia (SCZ). The polygenic score approach can be useful for testing this question. AIM: To assess the contribution of the polygenic risk scores for SCZ (PGS-SCZ) and polygenic scores for IQ (PGS-IQ) to the individual IQ and its difference from the mean IQ of the family (named family-IQ) through a family-based design in an FEP sample. METHODS: The PAFIP-FAMILIES sample (Spain) consists of 122 FEP patients, 131 parents, 94 siblings, and 176 controls. They all completed the WAIS Vocabulary subtest for IQ estimation and provided a DNA sample. We calculated PGS-SCZ and PGS-IQ using the continuous shrinkage method. To account for relatedness in our sample, we performed linear mixed models. We controlled for covariates potentially related to IQ, including age, years of education, sex, and ancestry principal components. RESULTS: FEP patients significantly deviated from their family-IQ. FEP patients had higher PGS-SCZ than other groups, whereas the relatives had intermediate scores between patients and controls. PGS-IQ did not differ between groups. PGS-SCZ significantly predicted the deviation from family-IQ, whereas PGS-IQ significantly predicted individual IQ. CONCLUSIONS: PGS-SCZ discriminated between different levels of genetic risk for the disorder and was specifically related to patients' lower IQ in relation to family-IQ. The genetic background of the disorder may affect neurocognition through complex pathological processes interacting with environmental factors that prevent the individual from reaching their familial cognitive potential.

Are Genetic and Environmental Risk Factors for Psychopathology Amplified in Children with Below-Average Intelligence? A Population-Based Twin Study.

There is a negative association between intelligence and psychopathology. We analyzed data on intelligence and psychopathology to assess this association in seven-year-old Dutch twin pairs (ranging from 616 to 14,150 depending on the phenotype) and estimated the degree to which genetic and environmental factors common to intelligence and psychopathology explain the association. Secondly, we examined whether genetic and environmental effects on psychopathology are moderated by intelligence. We found that intelligence, as assessed by psychometric IQ tests, correlated negatively with childhood psychopathology, as assessed by the DSM-oriented scales of the Child Behavior Check List (CBCL). The correlations ranged between - .09 and - .15 and were mainly explained by common genetic factors. Intelligence moderated genetic and environmental effects on anxiety and negative affect, but not those on ADHD, ODD, and autism. The heritability of anxiety and negative affect was greatest in individuals with below-average intelligence. We discuss mechanisms through which this effect could arise, and we end with some recommendations for future research.

Evaluation of genomic factors and early childhood stimulation on intelligence in children from a Brazilian birth cohort: The primary role of independent factors.

BACKGROUND: Childhood cognitive abilities are a predictor of health outcomes and adult income potential. Identifying factors associated with childhood intelligence and their interactions is essential in behavioral research. We assessed the impact of genetic variants and early child stimulation (ECS) on child intelligence and examined their possible interaction as potential modifiers of IQ in a population-based longitudinal study. METHODS: Participants of the 2004 Pelotas Birth Cohort study (N = 4231) underwent intelligent quotient (IQ) by WISC-III assessment at 6 years of age. At 24 and 48-months, mothers answered five ECS marker questions, whose sum was used to create a score. The polygenic score for intelligence (IQ-PGS) was constructed from the GWAS-weighted estimate of cognition. Association was assessed using multiple linear regression models adjusted for maternal, family, and child confounding variables. To explore the possible influence of skin color and ethnoracial classification, the regression models were stratified according to the skin color variable, as a sensitivity analysis. RESULTS: In the adjusted analysis, IQ-PGS (ß = 0.79, 95% confidence interval [95% CI] 0.26;1.31) as well as ECS (ß = 2.34; 95% CI: 1.76;2.92) were associated with IQ in this sample. The association between IQ-PGS and IQ was significant only in the white Brazilian group in the sensitivity analysis. However, there was no interaction between IQ-PGS and ECS on IQ (p(IQ-PGS x ECS) = 0.46). CONCLUSIONS: ECS did not modify the impact of genetic potential on intellectual development during childhood, suggesting that genetic factors and ECS exert independent effects on the IQ levels of children.

The causality of physical activity status and intelligence: A bidirectional Mendelian randomization study.

BACKGROUND: Observational studies suggest physical activity (PA) enhances intelligence, while sedentary behavior (SB) poses a risk. However, causality remains unclear. METHODS: We extracted genetic instruments from large genome-wide association studies summary data and employed an inverse-variance weighted (IVW) approach within a random-effects model as the primary method of Mendelian randomization (MR) analysis to estimate the overall effect of various physical activity statuses on intelligence. To assess IVW stability and MR sensitivity, we also utilized supplementary methods including weighted median, MR-Egger, and MR-PRESSO. Furthermore, multivariable MR analysis was conducted to examine the independent effects of each physical activity trait on intelligence. RESULTS: The MR primary results indicated that LST was negatively associated with intelligence (ß = -0.133, 95%CI: -0.177 to -0.090, p = 1.34×10-9), while SBW (ß = 0.261, 95% CI: 0.059 to 0.463, p = 0.011) may have a positive effect on intelligence; however, MVPA and SC did not show significant effects on intelligence. Inverse causality analyses demonstrated intelligence significantly influenced all physical activity states. CONCLUSIONS: Our study highlights a bidirectional causal relationship between physical activity states and intelligence.

Shifting as an executive function separate from updating and inhibition in old age: Behavioral and genetic evidence.

This study aimed to examine the organization of executive functions (EFs), specifically working memory updating, prepotent response inhibition, and mental-set shifting in old age, with a particular focus on determining whether the shifting function was behaviorally and genetically separated from the other functions. A total of 248 healthy older Chinese individuals participated, and multiple measures of executive functions were collected. Additionally, measures of fluid intelligence were included to explore the varying relationships between the three executive functions and this higher-order cognitive ability. Furthermore, genetic data were gathered and analyzed to investigate the associations between EFs and six candidate single-nucleotide polymorphisms (SNPs) mapped to dopaminergic, serotonergic, or glutamatergic genes. The results indicated that both the three-factor model and the two-factor model, which combined updating and inhibition, demonstrated a good fit. Furthermore, shifting was found to be behaviorally separated from the other two functions, and the correlation between shifting and fluid intelligence was smaller compared to the correlations between updating and inhibition with fluid intelligence. Moreover, the DRD2 SNPs showed significant associations with shifting, rather than with updating and inhibition. These findings provide evidence that shifting is distinct and separate from updating and inhibition, highlighting the diversity of EFs among older adults.

Causal associations and genetic overlap between COVID-19 and intelligence.

OBJECTIVE: COVID-19 might cause neuroinflammation in the brain, which could decrease neurocognitive function. We aimed to evaluate the causal associations and genetic overlap between COVID-19 and intelligence. METHODS: We performed Mendelian randomization (MR) analyses to assess potential associations between three COVID-19 outcomes and intelligence (N = 269 867). The COVID phenotypes included severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (N = 2 501 486), hospitalized COVID-19 (N = 1 965 329) and critical COVID-19 (N = 743 167). Genome-wide risk genes were compared between the genome-wide association study (GWAS) datasets on hospitalized COVID-19 and intelligence. In addition, functional pathways were constructed to explore molecular connections between COVID-19 and intelligence. RESULTS: The MR analyses indicated that genetic liabilities to SARS-CoV-2 infection (odds ratio [OR]: 0.965, 95% confidence interval [CI]: 0.939-0.993) and critical COVID-19 (OR: 0.989, 95% CI: 0.979-0.999) confer causal effects on intelligence. There was suggestive evidence supporting the causal effect of hospitalized COVID-19 on intelligence (OR: 0.988, 95% CI: 0.972-1.003). Hospitalized COVID-19 and intelligence share 10 risk genes within 2 genomic loci, including MAPT and WNT3. Enrichment analysis showed that these genes are functionally connected within distinct subnetworks of 30 phenotypes linked to cognitive decline. The functional pathway revealed that COVID-19-driven pathological changes within the brain and multiple peripheral systems may lead to cognitive impairment. CONCLUSIONS: Our study suggests that COVID-19 may exert a detrimental effect on intelligence. The tau protein and Wnt signaling may mediate the influence of COVID-19 on intelligence.

Intelligence quotient-genotype association in dystrophinopathies: A systematic review and meta-analysis.

AIMS: Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are associated with intelligence quotients (IQs) lower than the normative values, and it is suggested that IQ is negatively correlated with the number of affected isoforms (i.e., Dp427, Dp140 and Dp71). Therefore, the objective of this meta-analysis was to estimate the IQ, and the IQ-genotype association according to the altered dystrophin isoforms, in the population with BMD or DMD. METHODS: A systematic search in Medline, Web of Science, Scopus and the Cochrane Library was conducted from inception to March 2023. Observational studies that determined the IQ and/or the IQ by genotype in the population with BMD or DMD were included. Meta-analyses of IQ, IQ by genotype and IQ-genotype association by comparing IQ according to the genotype were conducted. The results are shown as the mean/mean differences and 95% confidence intervals. RESULTS: Fifty-one studies were included. The IQ in BMD was 89.92 (85.84, 94.01) and in DMD was 84.61 (82.97, 86.26). Moreover, the IQ for Dp427-/Dp140+/Dp71+ and Dp427-/Dp140-/Dp71+ was 90.62 (86.72, 94.53) and 80.73 (67.49, 93.98) in BMD, while the IQ for Dp427-/Dp140+/Dp71+, Dp427-/Dp140-/Dp71+ and Dp427-/Dp140-/Dp71- was 93.05 (89.42, 96.67), 81.78 (77.23, 86.32) and 49.19 (40.47, 57.90) in DMD. Finally, in DMD, Dp427-/Dp140-/Dp71+ vs Dp427-/Dp140+/Dp71+ and Dp427-/Dp140-/Dp71- vs Dp427-/Dp140-/Dp71+ were associated with -10.73 (-14.66, -6.81) and -36.14 (-48.87, -23.41) points, respectively. CONCLUSIONS: The IQ in BMD and DMD was lower than the normative values. Moreover, in DMD, there is a synergistic association between the number of affected isoforms and IQ.

A Longitudinal Analysis of Gene x Environment Interaction on Verbal Intelligence Across Adolescence and Early Adulthood.

The Scarr-Rowe hypothesis proposes that the heritability of intelligence is higher in more advantaged socioeconomic contexts. An early demonstration of this hypothesis was Rowe and colleagues (Rowe et al., Child Dev 70:1151-1162, 1999), where an interaction between the heritability of verbal intelligence and parental education was identified in adolescent siblings in Wave I of the National Longitudinal Study of Adolescent to Adult Health. The present study repeated their original analysis at Wave I using contemporary methods, replicated the finding during young adulthood at Wave III, and analyzed the interaction longitudinally utilizing multiple measurements. We examined parental education, family income, and peer academic environment as potential moderators. Results indicated increased heritability and decreased shared environmental variance of verbal intelligence at higher levels of parental education and peer academic environment in adolescence. Moreover, moderation by peer academic environment persisted into adulthood with its effect partially attributable to novel gene-environment interactions that arose in the process of cognitive development.

Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI. METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups. RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (median = 5, range: 2-10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, P = .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, P = 1.7 × 10-5; rs31771, P = 7.8 × 10-4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-P = 9.4 × 10-9), WM (rs17774009, meta-P = 4.2 × 10-9), and PS (rs77467524, meta-P = 1.5 × 10-8; rs17630683, meta-P = 2.0 × 10-8; rs73249323, meta-P = 3.1 × 10-8). CONCLUSIONS: Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors.

Structural architecture and brain network efficiency link polygenic scores to intelligence.

Intelligence is highly heritable. Genome-wide association studies (GWAS) have shown that thousands of alleles contribute to variation in intelligence with small effect sizes. Polygenic scores (PGS), which combine these effects into one genetic summary measure, are increasingly used to investigate polygenic effects in independent samples. Whereas PGS explain a considerable amount of variance in intelligence, it is largely unknown how brain structure and function mediate this relationship. Here, we show that individuals with higher PGS for educational attainment and intelligence had higher scores on cognitive tests, larger surface area, and more efficient fiber connectivity derived by graph theory. Fiber network efficiency as well as the surface of brain areas partly located in parieto-frontal regions were found to mediate the relationship between PGS and cognitive performance. These findings are a crucial step forward in decoding the neurogenetic underpinnings of intelligence, as they identify specific regional networks that link polygenic predisposition to intelligence.

A Bivariate Twin Study of Cortical Surface Area and Verbal and Nonverbal Intellectual Skills in Adolescence.

Understanding the biological basis of cognitive differences between individuals is the goal in human intelligence research. The surface area of the cortex is considered to be a key determinant of human intelligence. Adolescence is a period of development characterized by physiological, emotional, behavioral, and psychosocial changes, which is related to the recombination and optimization of the cerebral cortex, and cognitive ability changes significantly in children and adolescents. This study examined the effects of common genetic and environmental factors between the surface area of the cerebral cortex and intelligence in typical developing adolescents (twins, n = 114, age 12-18 years old). Cortical surface area data were parsed into subregions (i.e., frontal, parietal, occipital, and temporal areas) and intelligence into verbal and nonverbal skills. We found a phenotypic correlation between regional surface areas and verbal intelligence. No correlation was observed between regional surface areas and nonverbal intelligence, except for the occipital lobe and the right hemisphere. In the bivariate twin analyses, the differences in phenotypic correlation between regional surface areas and verbal intelligence were not due to unshared environmental effects or measurement error, but to genetic effects. In summary, the current study has broadened the previous genetic investigations of cognitive ability and cortical surface area.

Correlation of rs35753505 polymorphism in Neuregulin 1 gene with psychopathology and intelligence of people with schizophrenia.

BACKGROUND AND AIM: Schizophrenia is one of the most severe psychiatric disorders. About 0.5 to 1% of the world's population suffers from this non-Mendelian disorder. Environmental and genetic factors seem to be involved in this disorder. In this article, we investigate the alleles and genotypic correlation of mononucleotide rs35753505 polymorphism of Neuregulin 1 (NRG1), one of the selected genes of schizophrenia, with psychopathology and intelligence. MATERIALS AND METHODS: 102 independent and 98 healthy patients participated in this study. DNA was extracted by the salting out method and the polymorphism (rs35753505) were amplified by polymerase chain reaction (PCR). Sanger sequencing was performed on PCR products. Allele frequency analysis was performed using COCAPHASE software, and genotype analysis was performed using Clump22 software. RESULTS: According to our study's statistical findings, all case samples from the three categories of men, women, and overall participants significantly differed from the control group in terms of the prevalence of allele C and the CC risk genotype. The rs35753505 polymorphism significantly raised Positive and Negative Syndrome Scale (PANSS) test results, according to a correlation analysis between the two variables. However, this polymorphism led to a significant decrease in overall intelligence in case samples compared to control samples. CONCLUSION: In this study, it seems that the rs35753505 polymorphism of NRG1 gene has a significant role in the sample of patients with schizophrenia in Iran and also in psychopathology and intelligence disorders.

Brain volumes, thicknesses, and surface areas as mediators of genetic factors and childhood adversity on intelligence.

Although genetic and environmental factors influence general intelligence (g-factor), few studies examined the neuroanatomical measures mediating environmental and genetic effects on intelligence. Here, we investigate the brain volumes, cortical mean thicknesses, and cortical surface areas mediating the effects of the g-factor polygenic score (gPGS) and childhood adversity on the g-factor in the UK Biobank. We first examined the global and regional brain measures that contribute to the g-factor. Most regions contributed to the g-factor through global brain size. Parieto-frontal integration theory (P-FIT) regions were not more associated with the g-factor than non-PFIT regions. After adjusting for global brain size and regional associations, only a few regions predicted intelligence and were included in the mediation analyses. We conducted mediation analyses on global measures, regional volumes, mean thicknesses, and surface areas, separately. Total brain volume mediated 7.04% of the gPGS' effect on the g-factor and 2.50% of childhood adversity's effect on the g-factor. In comparison, the fraction of the gPGS and childhood adversity's effects mediated by individual regional volumes, surfaces, and mean thicknesses was 10-15 times smaller. Therefore, genetic and environmental effects on intelligence may be mediated to a larger extent by other brain properties.

A General Cognitive Ability Factor for the UK Biobank.

UK Biobank participants do not have a high-quality measure of intelligence or polygenic scores (PGSs) of intelligence to simultaneously examine the genetic and neural underpinnings of intelligence. We created a standardized measure of general intelligence (g factor) relative to the UK population and estimated its quality. After running a GWAS of g on UK Biobank participants with a g factor of good quality and without neuroimaging data (N = 187,288), we derived a g PGS for UK Biobank participants with neuroimaging data. For individuals with at least one cognitive test, the g factor from eight cognitive tests (N = 501,650) explained 29% of the variance in cognitive test performance. The PGS for British individuals with neuroimaging data (N = 27,174) explained 7.6% of the variance in g. We provided high-quality g factor estimates for most UK Biobank participants and g factor PGSs for UK Biobank participants with neuroimaging data.

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.

Bidirectional genetic overlap between bipolar disorder and intelligence.

BACKGROUND: Bipolar disorder (BD) is a highly heritable psychiatric illness exhibiting substantial correlation with intelligence. METHODS: To investigate the shared genetic signatures between BD and intelligence, we utilized the summary statistics from genome-wide association studies (GWAS) to conduct the bivariate causal mixture model (MiXeR) and conjunctional false discovery rate (conjFDR) analyses. Subsequent expression quantitative trait loci (eQTL) mapping in human brain and enrichment analyses were also performed. RESULTS: Analysis with MiXeR suggested that approximately 10.3K variants could influence intelligence, among which 7.6K variants were correlated with the risk of BD (Dice: 0.80), and 47% of these variants predicted BD risk and intelligence in consistent allelic directions. The conjFDR analysis identified 37 distinct genomic loci that were jointly associated with BD and intelligence with a conjFDR < 0.01, and 16 loci (43%) had the same directions of allelic effects in both phenotypes. Brain eQTL analyses found that genes affected by the "concordant loci" were distinct from those modulated by the "discordant loci". Enrichment analyses suggested that genes related to the "concordant loci" were significantly enriched in pathways/phenotypes related with synapses and sleep quality, whereas genes associated with the "discordant loci" were enriched in pathways related to cell adhesion, calcium ion binding, and abnormal emotional phenotypes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between BD and intelligence and identified multiple genomic loci and risk genes. This study provides hints for the mesoscopic phenotypes of BD and relevant biological mechanisms, promoting the knowledge of the genetic and phenotypic heterogeneity of BD. The essential value of leveraging intelligence in BD investigations is also highlighted.

Overlap between genetic variants associated with schizophrenia spectrum disorders and intelligence quotient: a systematic review.

BACKGROUND: To study whether there is genetic overlap underlying the risk for schizophrenia spectrum disorders (SSDs) and low intelligence quotient (IQ), we reviewed and summarized the evidence on genetic variants associated with both traits. METHODS: We performed this review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and preregistered it in PROSPERO. We searched the Medline databases via PubMed, PsycInfo, Web of Science and Scopus. We included studies in adults with a diagnosis of SSD that explored genetic variants (single nucleotide polymorphisms [SNPs], copy number variants [CNVs], genomic insertions or genomic deletions), estimated IQ and studied the relationship between genetic variability and both traits (SSD and IQ). We synthesized the results and assessed risk of bias using the Quality of Genetic Association Studies (Q-Genie) tool. RESULTS: Fifty-five studies met the inclusion criteria (45 case-control, 9 cross-sectional, 1 cohort), of which 55% reported significant associations for genetic variants involved in IQ and SSD. The SNPs more frequently explored through candidate gene studies were in COMT, DTNBP1, BDNF and TCF4. Through genome-wide association studies, 2 SNPs in CHD7 and GATAD2A were associated with IQ in patients with SSD. The studies on CNVs suggested significant associations between structural variants and low IQ in patients with SSD. LIMITATIONS: Overall, primary studies used heterogeneous IQ measurement tools and had small samples. Grey literature was not screened. CONCLUSION: Genetic overlap between SSD and IQ supports the neurodevelopmental hypothesis of schizophrenia. Most of the risk polymorphisms identified were in genes relevant to brain development, neural proliferation and differentiation, and synaptic plasticity.

General intelligence and executive functioning are overlapping but separable at genetic and molecular pathway levels: An analytical review of existing GWAS findings.

Understanding the genomic architecture and molecular mechanisms of cognitive functioning in healthy individuals is critical for developing tailored interventions to enhance cognitive functioning, as well as for identifying targets for treating impaired cognition. There has been substantial progress in uncovering the genetic composition of the general cognitive ability (g). However, there is an ongoing debate whether executive functioning (EF)-another key predictor of cognitive health and performance, is separable from general g. To provide an analytical review on existing findings on genetic influences on the relationship between g and EF, we re-analysed a subset of genome-wide association studies (GWAS) from the GWAS catalogue that used measures of g and EF as outcomes in non-clinical populations. We identified two sets of single nucleotide polymorphisms (SNPs) associated with g (1,372 SNPs across 12 studies), and EF (300 SNPs across 5 studies) at p<5x10-6. A comparative analysis of GWAS-identified g and EF SNPs in high linkage disequilibrium (LD), followed by pathway enrichment analyses suggest that g and EF are overlapping but separable at genetic variant and molecular pathway levels, however more evidence is required to characterize the genetic overlap/distinction between the two constructs. While not without limitations, these findings may have implications for navigating further research towards translatable genetic findings for cognitive remediation, enhancement, and augmentation.