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

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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.

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Acknowledgment

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. Data management and the specific analyses reported here were supported by 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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Authors and Affiliations

  1. Department of Medicine, University of Washington, Box 359780, 325 Ninth Avenue, Seattle, WA, 98104, USA

    Shubhabrata Mukherjee, Laura E. Gibbons, Thomas J. Montine & Paul K. Crane

  2. Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA

    Sungeun Kim, Vijay K. Ramanan, Kwangsik Nho & Andrew J. Saykin

  3. Department of Society, Human Development and Health, Harvard School of Public Health, Boston, MA, USA

    M. Maria Glymour

  4. Departments of Neurology and Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA

    Nilüfer Ertekin-Taner

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  1. Shubhabrata Mukherjee
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  2. Sungeun Kim
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  3. Vijay K. Ramanan
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  4. Laura E. Gibbons
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  7. Nilüfer Ertekin-Taner
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  8. Thomas J. Montine
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  9. Andrew J. Saykin
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for the Alzheimer’s Disease Neuroimaging Initiative

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Correspondence to Shubhabrata Mukherjee.

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Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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Table 4 Top SNPs for GWAS of executive functioning resilience
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Mukherjee, S., Kim, S., Ramanan, V.K. et al. Gene-based GWAS and biological pathway analysis of the resilience of executive functioning. Brain Imaging and Behavior 8, 110–118 (2014). https://doi.org/10.1007/s11682-013-9259-7

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