Genome‐wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test

Zhang, Huiping; Zhou, Hang; Lencz, Todd; Farrer, Lindsay A.; Kranzler, Henry R.

doi:10.1002/ajmg.b.32642

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…The associated variants near IGF1R are all African-specific according to the Genome Aggregation Database. 52 Interestingly, a GWAS of cognitive flexibility, an AD-linked phenotype, 53 identified a genome-wide significant association approximately 80 kilobases upstream of this rare variant signal in African American individuals but not in non-Hispanic White individuals, 54 lending support to this locus as an AD locus specific to African American individuals. IGF1R is a receptor for insulinlike growth factor I (IGF-I) controlling stress resistance, aging, and lifespan.…”

Section: Discussionmentioning

confidence: 99%

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel

Kunkle¹,

Schmidt²,

Klein³

et al. 2021

JAMA Neurol

185

148

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IMPORTANCECompared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. OBJECTIVETo identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. DESIGN, SETTING, AND PARTICIPANTSThis genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. MAIN OUTCOMES AND MEASURES Diagnosis of Alzheimer disease.RESULTS A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10 −7 ), near the immune response gene ALCAM (3q13; P = 9.3 × 10 −7 ), within GPC6 (13q31; P = 4.1 × 10 −7 ), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10 −7 ), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10 −9 ) and 6 additional loci with suggestive significance (P Յ 5 × 10 −7 ) such as API5 at 11p12 (P = 8.8 × 10 −8 ) and RBFOX1 at 16p13 (P = 5.4 × 10 −7 ) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.CONCLUSIONS AND RELEVANCE While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

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Section: Discussionmentioning

confidence: 99%

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel

Kunkle¹,

Schmidt²,

Klein³

et al. 2021

JAMA Neurol

185

148

View full text Add to dashboard Cite

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“…The summary statistics which met inclusion criteria are presented in Table 1. While summary statistics for the Wisconsin Card Sorting Test (Zhang et al 2018), the PsyCourse Study’s Trail Making Part B and Backwards Digit Span, (Wendel et al, 2021) and the CHARGE consortium’s Trail-Making Part B were also obtained, these failed to show significant SNP heritability in LDSC and so were excluded from further analysis. In addition to their factor score GWAS statistics, Hatoum et al (2022) made available summary statistics for GWAS of the individual tests that contributed to it.…”

Section: Methodsmentioning

confidence: 99%

“…As a consequence, marked heterogeneity exists in the approaches to measuring EF phenotypes used in GWAS. Across the 7 GWAS of EF as measured through cognitive tests that could be identified in the literature, only two, trail-marking part B and backwards digit span, were used in more than one study (Ibrahim-Verbaas et al, 2016; Zhang et al 2018; Donati, Dumontheil, and Meaburn, 2019; Wendel et al, 2021; Hatoum et al, 2022; Dueker et al, 2023; Arnatkeviciute et al, 2023). As these GWAS have largely been performed on separate, weakly-correlated tests rather than latent factors, it is difficult to determine if they are measuring constructs similar to those found elsewhere in EF literature or even in other GWAS.…”

Section: Introductionmentioning

confidence: 99%

GenomicSEM Modelling of Diverse Executive Function GWAS Improves Gene Discovery

Perry,

Chevalier,

Luciano

2024

Preprint

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Previous research has supported the use of factor scores as the gold-standard in measuring executive function. However, for logistical reasons genome-wide association studies (GWAS) of executive function have largely eschewed factor scores in favour of singular task measures. As low correlations have traditionally been found between individual executive function (EF) tests, it is unclear whether these GWAS have truly been measuring the same construct. In this study, we addressed this question by performing a factor analysis on summary statistics from nine GWAS of EF taken from four studies, using GenomicSEM. Models were able to capture the classic three factors of inhibition, working memory, and set-shifting, although set-shifting and inhibition could be merged without negatively impacting model fit. Furthermore, the GWAS performed on a common factor model identified 63 new genomic risk loci beyond what was found in the constituent GWAS reaching genome-wide significance, resulting in 18 newly mapped EF genes. The majority of these have previous associations with brain morphology but no established associations with cognitive performance. These results help to clarify the underlying genetic structure of EF and support the idea that EF GWAS are capable of measuring genetic variance related to latent EF constructs even when not using factor scores. Furthermore, they demonstrate that GenomicSEM can combine GWAS with divergent and non-ideal measures of the same phenotype to improve statistical power.

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Mind-body exercise affects attention switching and sustained attention in female adults with Attention Deficit/Hyperactivity Disorder: A randomized, controlled trial with 6-month follow-up

2022

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Genome‐wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test

Cited by 5 publications

References 42 publications

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel

GenomicSEM Modelling of Diverse Executive Function GWAS Improves Gene Discovery

Mind-body exercise affects attention switching and sustained attention in female adults with Attention Deficit/Hyperactivity Disorder: A randomized, controlled trial with 6-month follow-up

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