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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2007

Open Access 01-09-2007 | Research

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

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

Published in: BMC Medical Genetics | Special Issue 1/2007

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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.
Appendix
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Metadata
Title
Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study
Authors
Sudha Seshadri
Anita L DeStefano
Rhoda Au
Joseph M Massaro
Alexa S Beiser
Margaret Kelly-Hayes
Carlos S Kase
Ralph B D'Agostino Sr
Charles DeCarli
Larry D Atwood
Philip A Wolf
Publication date
01-09-2007
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue Special Issue 1/2007
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-8-S1-S15

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