Brain Imaging and Behavior

, Volume 6, Issue 4, pp 621–633

Genetic architecture of resilience of executive functioning

  • Shubhabrata Mukherjee
  • Sungeun Kim
  • Laura E. Gibbons
  • Kwangsik Nho
  • Shannon L. Risacher
  • M. Maria Glymour
  • Christian Habeck
  • Grace J. Lee
  • Elizabeth Mormino
  • Nilüfer Ertekin-Taner
  • Thomas J. Montine
  • Charles DeCarli
  • Andrew J. Saykin
  • Paul K. Crane
  • for the Alzheimer’s Disease Neuroimaging Initiative
ADNI: Friday Harbor 2011 Workshop SPECIAL ISSUE

DOI: 10.1007/s11682-012-9184-1

Cite this article as:
Mukherjee, S., Kim, S., Gibbons, L.E. et al. Brain Imaging and Behavior (2012) 6: 621. doi:10.1007/s11682-012-9184-1

Abstract

The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H2 = 0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value = 4.31 × 10-7). rs3748348 is in strong linkage disequilibrium (D′ of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the α-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value = 7 × 10-7). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience.

Keywords

Memory Executive functioning Alzheimer’s disease Psychometrics Resilience GWAS 

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Shubhabrata Mukherjee
    • 1
  • Sungeun Kim
    • 3
  • Laura E. Gibbons
    • 1
  • Kwangsik Nho
    • 3
  • Shannon L. Risacher
    • 3
  • M. Maria Glymour
    • 4
  • Christian Habeck
    • 5
  • Grace J. Lee
    • 6
  • Elizabeth Mormino
    • 7
  • Nilüfer Ertekin-Taner
    • 8
  • Thomas J. Montine
    • 2
  • Charles DeCarli
    • 9
  • Andrew J. Saykin
    • 3
  • Paul K. Crane
    • 1
  • for the Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Department of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Department of PathologyUniversity of WashingtonSeattleUSA
  3. 3.Center for Neuroimaging, Department of Radiology and Imaging SciencesIndiana University School of MedicineIndianapolisUSA
  4. 4.Department of Society, Human Development, and HealthHarvard School of Public HealthBostonUSA
  5. 5.Cognitive Neuroscience Division, The Taub Institute for Research on Aging and Alzheimer’s DiseaseColumbia UniversityNew YorkUSA
  6. 6.Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, Department of NeurologyDavid Geffen School of Medicine at UCLALos AngelesUSA
  7. 7.Helen Wills Neuroscience InstituteUniversity of California BerkeleyBerkeleyUSA
  8. 8.Departments of Neurology and NeuroscienceMayo Clinic FloridaJacksonvilleUSA
  9. 9.Department of Neurology and Center for NeuroscienceUniversity of California at DavisSacramentoUSA

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