Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function

Smeland, Olav B.; Frei, Oleksandr; Kauppi, Karolina; Hill, W. David; Li, Wen; Wang, Yunpeng; Krull, Florian; Bettella, Francesco; Eriksen, Jon Alm; Witoelar, Aree; Davies, Gail; Fan, Chun Chieh; Thompson, Wesley K.; Lam, Max; Lencz, Todd; Chen, Chi‐Hua; Ueland, Torill; Jönsson, Erik G.; Djurovic, Srdjan; Deary, Ian J.; Dale, Anders M.; Andreassen, Ole A.

doi:10.1001/jamapsychiatry.2017.1986

Cited by 120 publications

(128 citation statements)

References 58 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…Uncovering the molecular genetic basis of individual differences in cognitive performance can have a significant impact on our understanding of neuropsychiatric disorders, which are both phenotypically (Burdick et al, 2011; Ferreri et al, 2011; Keefe and Harvey, 2012; Snyder, 2013) and genetically (Lencz et al, 2014; Smeland et al, 2017; Stergiakouli et al, 2017) correlated with cognition, as well as numerous non-psychiatric health-relevant phenotypes (Hagenaars et al, 2016) which also demonstrate significant genetic correlations with cognitive function. Here, we have presented the largest GWAS of cognition to date, with 107,207 individuals phenotypically characterized for performance on standardized tests measuring general cognitive ability.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

Summary 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 GCA. 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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Over 50% of our patients had diagnoses of BP disorder, so the significant correlation based on UKB data is likely related to cognitive features, and not to specific symptomatic or syndromal factors. Also, of note, the cognition GWAS in the COGENT study was found to manifest genomic correlations with both SZ and bipolar BP (Smeland et al, ). Furthermore, previous genetic studies focusing on SZ (Burdick et al, ) and BP (Burdick et al, ) similarly identified genes that are strongly linked to cognition as well as the disorders of interest.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, and by leveraging results for several education‐related phenotypes, a multivariate GWAS of cognitive performance detected hundreds of additional genome‐wide significant loci not observed for cognitive performance alone (Lee et al, ). A combined analysis of COGENT data and results from the Psychiatric Genomics Consortium (PGC) study of SZ (Schizophrenia Working Group of the Psychiatric Genomics, Consortium, ) identified 21 genomic loci overlapping with SZ risk and global cognitive performance in the COGENT database (Smeland et al, ). The corresponding meta‐analyses did not, however, examine genetics of performance‐based assessment of cognitive abilities in cases with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder

Harvey

Sun

et al. 2019

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome‐wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome‐wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition‐related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

show abstract

“…In another study, we used the same conditional FDR approach and found substantial polygenetic overlap between SCZ and the cognitive traits of general cognitive function, verbal‐numeric reasoning and reaction time (Smeland, Frei, et al ., ). The conjunctional FDR analyses revealed 21 loci shared between SCZ and cognitive traits (general cognitive function 14, verbal numeric reasoning two and reaction time six).…”

Section: Shared Genetic Basis Between Scz and Cognitionmentioning

confidence: 99%

“…Recently, we have been able identify specific genetic regions jointly influencing SCZ risk and cognitive traits (Smeland, Frei, Kauppi et al ., ) and educational attainment (Le Hellard, Wang, Witoelar et al ., ), by taking advantage of novel Bayesian statistical tools (Andreassen, Thompson, et al ., ; Liu et al ., ; Schork et al ., ). We applied the conditional FDR method in a combined analysis of GWASs of SCZ and educational attainment, a proxy phenotype associated with cognitive function, to study overlapping genes with SCZ (Le Hellard et al ., ).…”

Section: Shared Genetic Basis Between Scz and Cognitionmentioning

confidence: 99%

How can genetics help understand the relationship between cognitive dysfunction and schizophrenia?

Smeland

Andreassen

2018

Scandinavian J Psychology

Self Cite

View full text Add to dashboard Cite

A. (2018). How can genetics help understand the relationship between cognitive dysfunction and schizophrenia? Scandinavian Journal of Psychology, 59,[26][27][28][29][30][31] Despite the consistent finding that cognitive dysfunction is a core characteristic of schizophrenia (SCZ), little is known about the underlying pathophysiology. Recent progress in human genetics, driven by large genome-wide association studies (GWAS), has provided new data about the genetic architecture of complex human traits, including cognition and SCZ. Novel analytical tools have provided unprecedented opportunities to leverage the large amount of information from GWAS. Here we review the latest findings related to genetic architecture and risk genes of SCZ and cognitive functions, and recent findings of overlapping genetic factors. The recent GWAS of SCZ implicate over 100 risk gene loci, each with a small effect. A similar genetic architecture seems to be present in cognitive domains, suggesting that these phenotypes are highly polygenic. Further, GWAS have revealed more than 20 gene loci associated with cognitive traits, including intelligence, general cognition (g-factor), reaction time and verbal-numerical reasoning. Several gene loci have been implicated in educational attainment, a proxy measure of cognitive function. Recently, overlapping gene loci were found between education and SCZ, and between SCZ and cognitive traits, suggesting common genetic risk between SCZ and cognitive dysfunction. Mathematical modeling of GWAS of cognition and SCZ indicate that only a fraction of the heritability is identified. The evidence suggests a polygenic architecture for SCZ and cognitive functions, and a large degree of shared genetic risk. This indicates novel molecular genetic mechanisms and strengthens the notion that SCZ is more likely a part of the normal distribution and not a separate entity.

show abstract

Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function

Abstract: The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

Cited by 120 publications

References 58 publications

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

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

Genome‐wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder

How can genetics help understand the relationship between cognitive dysfunction and schizophrenia?

Contact Info

Product

Resources

About