Genetic correlates of brain aging on MRI and cognitive test measures: A genome-wide association and linkage analysis in the framingham study

Sudha Seshadri, Anita L. de Stefano, Rhoda Au, Joseph M. Massaro, Alexa S. Beiser, Margaret Kelly-Hayes, Carlos S. Kase, Ralph B. D'Agostino, Charles DeCarli, Larry D. Atwood, Philip A. Wolf

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Background: Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. Methods: A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999-2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. Results: The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously reported linkage of WMH on chromosome 4 and describe linkage of reading performance to a marker on chromosome 18 (GATA11A06), previously linked to dyslexia (LOD scores = 2.2 and 5.1). Conclusion: Our results suggest that genes associated with clinical neurological disease also have detectable effects on subclinical phenotypes. These hypothesis generating data illustrate the use of an unbiased approach to discover novel pathways that may be involved in brain aging, and could be used to replicate observations made in other studies.

Original languageEnglish (US)
Article numberS15
JournalBMC Medical Genetics
Volume8
Issue numberSUPPL. 1
DOIs
StatePublished - Sep 19 2007

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Genome-Wide Association Study
Endophenotypes
Magnetic Resonance Imaging
Single Nucleotide Polymorphism
Alzheimer Disease
Stroke
Brain
Genes
Dementia
Reading
Phenotype
Chromosomes, Human, Pair 18
Dyslexia
Chromosomes, Human, Pair 4
Amyloid beta-Protein Precursor
Oligonucleotide Array Sequence Analysis
Gene Frequency
Microsatellite Repeats
Linear Models
Analysis of Variance

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)

Cite this

Seshadri, S., de Stefano, A. L., Au, R., Massaro, J. M., Beiser, A. S., Kelly-Hayes, M., ... Wolf, P. A. (2007). Genetic correlates of brain aging on MRI and cognitive test measures: A genome-wide association and linkage analysis in the framingham study. BMC Medical Genetics, 8(SUPPL. 1), [S15]. https://doi.org/10.1186/1471-2350-8-S1-S15

Genetic correlates of brain aging on MRI and cognitive test measures : A genome-wide association and linkage analysis in the framingham study. / Seshadri, Sudha; de Stefano, Anita L.; Au, Rhoda; Massaro, Joseph M.; Beiser, Alexa S.; Kelly-Hayes, Margaret; Kase, Carlos S.; D'Agostino, Ralph B.; DeCarli, Charles; Atwood, Larry D.; Wolf, Philip A.

In: BMC Medical Genetics, Vol. 8, No. SUPPL. 1, S15, 19.09.2007.

Research output: Contribution to journalArticle

Seshadri, S, de Stefano, AL, Au, R, Massaro, JM, Beiser, AS, Kelly-Hayes, M, Kase, CS, D'Agostino, RB, DeCarli, C, Atwood, LD & Wolf, PA 2007, 'Genetic correlates of brain aging on MRI and cognitive test measures: A genome-wide association and linkage analysis in the framingham study', BMC Medical Genetics, vol. 8, no. SUPPL. 1, S15. https://doi.org/10.1186/1471-2350-8-S1-S15
Seshadri, Sudha ; de Stefano, Anita L. ; Au, Rhoda ; Massaro, Joseph M. ; Beiser, Alexa S. ; Kelly-Hayes, Margaret ; Kase, Carlos S. ; D'Agostino, Ralph B. ; DeCarli, Charles ; Atwood, Larry D. ; Wolf, Philip A. / Genetic correlates of brain aging on MRI and cognitive test measures : A genome-wide association and linkage analysis in the framingham study. In: BMC Medical Genetics. 2007 ; Vol. 8, No. SUPPL. 1.
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AU - Beiser, Alexa S.

AU - Kelly-Hayes, Margaret

AU - Kase, Carlos S.

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