Gene-based GWAS and biological pathway analysis of the resilience of executive functioning

Shubhabrata Mukherjee; Sungeun Kim; Vijay K. Ramanan; Laura E. Gibbons; Kwangsik Nho; M. Maria Glymour; Nilüfer Ertekin-Taner; Thomas J. Montine; Andrew J. Saykin; Paul K. Crane

doi:10.1007/s11682-013-9259-7

Gene-based GWAS and biological pathway analysis of the resilience of executive functioning

Shubhabrata Mukherjee, Sungeun Kim, Vijay K. Ramanan, Laura E. Gibbons, Kwangsik Nho, M. Maria Glymour, Nilüfer Ertekin-Taner, Thomas J. Montine, Andrew J. Saykin, Paul K. Crane

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23 Scopus citations

Abstract

Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123 = 2.8 × 10^-6) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) < 0.05). Gene-based analyses found a genome-wide significant association between RNASE13 and EF resilience (p = 1.33 × 10^-7). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density, etc., were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience.

Original language	English (US)
Pages (from-to)	110-118
Number of pages	9
Journal	Brain Imaging and Behavior
Volume	8
Issue number	1
DOIs	https://doi.org/10.1007/s11682-013-9259-7
State	Published - Mar 2014

Keywords

Alzheimer's disease
Executive functioning
Genes
Memory
Pathways
Resilience

ASJC Scopus subject areas

Radiology Nuclear Medicine and imaging
Neurology
Cognitive Neuroscience
Clinical Neurology
Cellular and Molecular Neuroscience
Psychiatry and Mental health
Behavioral Neuroscience

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10.1007/s11682-013-9259-7

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title = "Gene-based GWAS and biological pathway analysis of the resilience of executive functioning",

abstract = "Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123 = 2.8 × 10-6) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) < 0.05). Gene-based analyses found a genome-wide significant association between RNASE13 and EF resilience (p = 1.33 × 10-7). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density, etc., were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience.",

keywords = "Alzheimer's disease, Executive functioning, Genes, Memory, Pathways, Resilience",

author = "Shubhabrata Mukherjee and Sungeun Kim and Ramanan, {Vijay K.} and Gibbons, {Laura E.} and Kwangsik Nho and Glymour, {M. Maria} and Nil{\"u}fer Ertekin-Taner and Montine, {Thomas J.} and Saykin, {Andrew J.} and Crane, {Paul K.}",

note = "Funding Information: NIH grant R01 AG029672 (Paul Crane, PI), R13 AG030995 (Mungas), and P50 AG05136 (Montine), R01 AG032990 and P50 AG016574 (Crane), from the NIA as well as NIA R01 AG19771 (Saykin) and P30 AG10133 (Saykin/Ghetti).",

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AU - Nho, Kwangsik

AU - Glymour, M. Maria

AU - Ertekin-Taner, Nilüfer

AU - Montine, Thomas J.

AU - Saykin, Andrew J.

AU - Crane, Paul K.

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N2 - Resilience in executive functioning (EF) is characterized by high EF measured by neuropsychological test performance despite structural brain damage from neurodegenerative conditions. We previously reported single nucleotide polymorphism (SNP) genome-wide association study (GWAS) results for EF resilience. Here, we report gene- and pathway-based analyses of the same resilience phenotype, using an optimal SNP-set (Sequence) Kernel Association Test (SKAT) for gene-based analyses (conservative threshold for genome-wide significance = 0.05/18,123 = 2.8 × 10-6) and the gene-set enrichment package GSA-SNP for biological pathway analyses (False discovery rate (FDR) < 0.05). Gene-based analyses found a genome-wide significant association between RNASE13 and EF resilience (p = 1.33 × 10-7). Genetic pathways involved with dendritic/neuron spine, presynaptic membrane, postsynaptic density, etc., were enriched with association to EF resilience. Although replication of these results is necessary, our findings indicate the potential value of gene- and pathway-based analyses in research on determinants of cognitive resilience.

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Gene-based GWAS and biological pathway analysis of the resilience of executive functioning

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