Genome-wide scan in Hispanics highlights candidate loci for brain white matter hyperintensities

摘要

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 ?5) and 5 genes from the gene-based analysis with p ?3. One SNP (rs9957475 in GATA6 ) and 1 gene ( UBE2C ) demonstrated evidence of association ( p ?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. White matter hyperintensities (WMHs) are frequently detected by MRI in the aging brain 1 and are associated with a range of negative health outcomes. 2 , – 6 Prevalence ranges from 40% to 70% in the fifth decade 7 and increases with age. It is important that Hispanics and African Americans have shown more severe WMHs than ancestral Europeans. 8 Although heterogeneous in etiology, there is a consistent link between WMH burden and cerebrovascular risk factors, as well as with retinal microvascular abnormalities and vascular pathology. 9 Thus, WMHs could be considered a quantitative marker of small vessel injury. 10 Moreover, WMHs have a significant genetic component, with heritability estimates from 0.45 to 0.80. 10 , – 13 Identifying genetic determinants of WMHs has been a challenge. Linkage studies have yielded conflicting findings regarding the genetic loci influencing WMHs. 12 , – 14 The most consistently replicated locus identified for WMHs is on chromosome 17q25 and was first identified in ～9,500 individuals of European descent. 15 This locus was later replicated and additional loci on chromosomes 10q24 and 2p21 identified. 16 A multiethnic meta-analysis, including ～2,000 African Americans, ～800 Hispanics, and ～400 Asians, identified additional loci on chromosomes 1q22 and 2p16. 16 Although Hispanics and African Americans show more severe WMHs than Europeans, 8 these populations have not been the focus of genetic discovery. To address this, we performed a genome-wide association scan to identify genetic variants influencing WMHs in Hispanics in 2 community-based cohorts from the Northern Manhattan Study (NOMAS) and the Washington Heights–Inwood Columbia Aging Project (WHICAP).