Albert Hofman

Journal Article Epidemiology of Alzheimer's Disease Get access Monique M. B. Breteler, Monique M. B. Breteler Department of Epidemiology and Biostatistics, Erasmus University Medical SchoolRotterdam, The Netherlands Dr. M. M. B. Breteler, Department of Epidemiology and Biostatistics, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Jules J. Claus, Jules J. Claus Department of Epidemiology and Biostatistics, Erasmus University Medical SchoolRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Cornelia M. van Duijn, Cornelia M. van Duijn Department of Epidemiology and Biostatistics, Erasmus University Medical SchoolRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Lenore J. Launer, Lenore J. Launer Department of Epidemiology and Biostatistics, Erasmus University Medical SchoolRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Albert Hofman Albert Hofman Department of Epidemiology and Biostatistics, Erasmus University Medical SchoolRotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Epidemiologic Reviews, Volume 14, Issue 1, 1992, Pages 59–82, https://doi.org/10.1093/oxfordjournals.epirev.a036092 Published: 01 March 1992 Article history Received: 29 November 1991 Published: 01 March 1992 Revision received: 09 July 1992

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.