Published Online
on December 1, 2005

A more recent version of this article appeared on January 1, 2006

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Submitted on September 16, 2005
Accepted on October 5, 2005

Genome-Wide Scan for White Matter Hyperintensity. The Framingham Heart Study

Anita L. DeStefano PhD^*; Larry D. Atwood PhD; Joseph M. Massaro PhD; Nancy Heard-Costa PhD; Alexa Beiser PhD; Rhoda Au PhD; Philip A. Wolf MD; and Charles DeCarli MD

From the Department of Biostatistics (A.L.D., L.D.A., J.M.M., A.B.), Boston University School of Public Health, Boston, Mass; the Department of Neurology (A.L.D., L.D.A., N.H.-C., R.A., P.A.W.), Boston University School of Medicine, Boston, Mass; the Department of Mathematics and Statistics (J.M.M.), Boston University, Boston, Mass; Department of Neurology and Center for Neuroscience (C.D.), University of California at Davis, Sacramento, Calif.

^* To whom correspondence should be addressed. E-mail: adestef{at}bu.edu.

Background and Purpose--White matter hyperintensity (WMH) volume is associated with aging and cerebrovascular disease and has been demonstrated to have a high heritability in the Framingham Heart Study as well as in other studies. We performed a genome-wide linkage analysis to identify chromosomal regions that may harbor genes influencing WMH in a family-based sample of the Framingham Heart Study.

Methods--Brain magnetic resonance scans were performed, and WMH and total cranial volume (TCV) were quantified as previously described on 2259 cohort and offspring participants. The outcome used for linkage analysis was an age specific (within 10-year age groups) z-score for the natural logarithm of the ratio of WMH to TCV. This z-score was based on 2230 individuals after excluding 26 participants with neurological conditions other than stroke and 3 individuals whose ages were out of range. Variance component linkage analysis included 747 individuals (mean age=62.16±12.43 years) with both magnetic resonance measure and genotype information in 237 families. Mean percent WMH to TCV was 0.098±0.175 with a range of 0.00025% to 1.37% in the linkage analysis subjects.

Results--A maximum multipoint logarithm of the odds (LOD) score=3.69, which indicates significant evidence of linkage, was observed at 4 cM on chromosome 4. A suggestive peak with LOD=1.78 was observed at 95 cM on chromosome 17.

Conclusion--We have significant evidence that a gene influencing WMH volume is located on chromosome 4 of the human genome.

Key words: aging • cerebrovascular disorders • linkage (genetics)

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