Genome‐wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test |
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| Authors: | Huiping Zhang Hang Zhou Todd Lencz Lindsay A. Farrer Henry R. Kranzler Joel Gelernter |
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| Affiliation: | 1. Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts;2. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts;3. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut;4. Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, New York;5. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts;6. Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts;7. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts;8. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts;9. Department of Psychiatry, VISN4 MIRECC, Crescenz VAMC, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;10. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut;11. Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut;12. VA Medical Center, 116/A, VA Connecticut Healthcare System, West Haven, Connecticut |
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| Abstract: | Cognitive flexibility is a critical component of executive function and is strongly influenced by genetic factors. We conducted a genome‐wide association study of cognitive flexibility (as measured by perseverative errors on the Wisconsin Card Sorting Test) in two sets of African American (AA) and European American (EA) subjects (Yale‐Penn‐1: 1,411 AAs/949 EAs; Yale‐Penn‐2: 1,178 AAs/1,335 EAs). We examined the association of cognitive flexibility with genotyped or imputed SNPs across the genome. In AAs, two correlated common single nucleotide polymorphisms (SNPs) (rs7165213/rs35633795) in the downstream region of the noncoding gene LOC101927286 on chromosome 15 showed genome‐wide significant (GWS) associations with cognitive flexibility (Yale‐Penn‐1: p = 6.0 × 10?9/1.3 × 10?8; Yale‐Penn‐2: p = .029/.010; meta‐analysis: p = 4.2 × 10?7/1.0 × 10?7) in the same effect direction. In EAs, no GWS associations were observed. Enriched gene sets identified by Data‐driven Expression‐Prioritized Integration for Complex Traits (DEPICT) analysis of the top SNPs (pmeta‐analysis < 10?5) included the signalosome and ubiquitin‐specific peptidase 9, X‐linked (USP9X) subnetwork in AAs, and abnormal frontal and occipital bone morphology in EAs. We also performed polygenic risk score (PRS) analysis to examine the genetic correlation of cognition‐proxy phenotypes (general cognitive function, education attainment, childhood intelligence, and infant head circumference) and cognitive flexibility in EAs. The PRS derived from general cognitive function‐associated SNPs was significantly associated with cognitive flexibility. Nongenetic factors (age, education, sex, and tobacco recency) also exerted significant effects on cognitive flexibility. Our study demonstrates that both genetic and nongenetic factors impact cognitive flexibility, and variants in genes involved in protein degradation and brain development may contribute to population variation in cognitive function. |
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| Keywords: | cognitive flexibility enrichment analysis genome‐wide association study polygenic risk score Wisconsin Card Sorting Test |
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