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Genome-wide scan in Hispanics highlights candidate loci for brain white matter hyperintensities
Ashley Beecham1, Chuanhui Dong1, Clinton B Wright1
1John T. McDonald Department of Human Genetics (A.B., L.W., S.H.B., R.L.S.), John P Hussman Institute for Human Genomics (A.B., N.D., L.W., S.H.B.), Evelyn F. McKnight Brain Institute (C.D., C.B.W., T.R., R.L.S.), Department of Neurology (C.D., C.B.W., T.R., R.L.S.), and Department of Epidemiology and Public Health (C.B.W., T.R., R.L.S.), Miller School of Medicine, University of Miami, FL; Gertrude H. Sergievsky Center (A.M.B., R.M.), Taub Institute for Research on Alzheimer's Disease and the Aging Brain (A.M.B., R.M.), and Department of Neurology (A.M.B., R.M.), College of Physicians and Surgeons, Columbia University, New York; and Department of Neurology and Center for Neuroscience (C.D.), University of California at Davis, Sacramento.
Objective:
To investigate genetic variants influencing white matter hyperintensities (WMHs) in the understudied Hispanic population.
Methods:
Using 6.8 million single nucleotide polymorphisms (SNPs), we conducted a genome-wide association study (GWAS) to identify SNPs associated with WMH volume (WMHV) in 922 Hispanics who underwent brain MRI as a cross-section of 2 community-based cohorts in the Northern Manhattan Study and the Washington Heights-Inwood Columbia Aging Project. Multiple linear modeling with PLINK was performed to examine the additive genetic effects on ln(WMHV) after controlling for age, sex, total intracranial volume, and principal components of ancestry. Gene-based tests of association were performed using VEGAS. Replication was performed in independent samples of Europeans, African Americans, and Asians.
Results:
From the SNP analysis, a total of 17 independent SNPs in 7 genes had suggestive evidence of association with WMHV in Hispanics (p < 1 × 10-5) and 5 genes from the gene-based analysis with p < 1 × 10-3. One SNP (rs9957475 in GATA6) and 1 gene (UBE2C) demonstrated evidence of association (p < 0.05) in the African American sample. Four SNPs with p < 1 × 10-5 were shown to affect binding of SPI1 using RegulomeDB.
Conclusions:
This GWAS of 2 community-based Hispanic cohorts revealed several novel WMH-associated genetic variants. Further replication is needed in independent Hispanic samples to validate these suggestive associations, and fine mapping is needed to pinpoint causal variants.
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