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

Abstract

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.

The Associations of PMF1, ICAM1, AGT, TRIM65, FBF1, and ACOX1 Variants With Leukoaraiosis in Chinese Population

“…Consistent with those genome-wide association studies and our previous replication study which aimed to verify the top risk variants identified in the first GWAS study in European population (Hofer et al, 2015; Huang et al, 2016; Traylor et al, 2016; Beecham et al, 2017), this study also did not find any significantly positive associations of those strongest and suggestive risk genes that were identified in the multi-ethnic GWAS with LA in this Chinese population. Even the strongest WMH-associated variant (rs7214628 located in TRIM65 gene in 17q25 locus) which holds the strongest significance of p < 2.7E-19 and p < 5.1E-19 in European individuals and multi-ethnic populations, respectively (Verhaaren et al, 2015), also showed a lack of significant and detrimental effect on LA in the present study.…”

“…Other single nucleotide polymorphisms including rs7214628 in TRIM65 and rs78857879 in EFEMP1 had also been verified at genome-wide significance level by one later genome-wide meta-analysis study in overall combined community populations with stroke patients of European ancestry (Traylor et al, 2016). However, most of those SNPs could not be replicated by three recently published GWAS studies in independent populations (such as whites of European descent, African Americans, or Hispanic participants) to date (Hofer et al, 2015; Traylor et al, 2016; Beecham et al, 2017). On the contrary, they identified a large number of novel WMH-associated loci including four genome-wide significant genes ( NBEAL1 , EVL , C1QL1 , and COL4A2 ) and 12 suggestive genes ( CDC7 , ST6GAL2 , GATA6 , GFRA4 , TRIM6 , WFDC3 , FAM118A , UBE2C , PTPLA , RGPD4 , ALMS1 , and ZNF280D ), as well as four suggestive variants (rs10883817 in the introns of AS3MT , CNNM2 , and NT5C2 ; rs4761974 in close proximity to SLC4A8 ; rs6135309 in the intron of MACROD2 ; and rs7664442 located in the intergenic region near GBA3 ) (Hofer et al, 2015; Traylor et al, 2016; Beecham et al, 2017).…”

Integrated analysis of microRNA and mRNA expression profiling identifies BAIAP3 as a novel target of dysregulated hsa-miR-1972 in age-related white matter lesions

“…Although large-scale genetic studies of European descendants have identified many risk genes and single nucleotide polymorphisms (SNPs) in European descent, a small amount of SNPs from those risk genes has been confirmed in cross-ethnic genetic studies [ 22 , 24 , 25 , 27 , 29 – 35 ]. This not only indicates significant ethnic differences in LA susceptibility but also suggests a limited contribution from SNPs to LA pathogenesis.…”

Representation of Older Latinxs in Cohort Studies at the Rush Alzheimer’s Disease Center

“…Researchers across the USA have contributed significantly to the field of Latinx health and aging and continue to build evidence in this area (Table 1). For example, longitudinal studies of diverse populations have included non-demented Latinxs along with non-Latinx blacks and whites to examine stroke and related risk factors [9][10][11], as well as aging and incident dementia [9,[12][13][14][15]. Research has also focused on blood biomarkers of older Latinxs from select countries of origin with and without a diagnosis of mild cognitive impairment (MCI) or Alzheimer's dementia [4,[16][17][18][19][20].…”

“…Through 5 cohort studies, the Rush Alzheimer's Disease Center (RADC) [8][9][10] aims to conceptualize and conduct needed studies of older adults across diverse racial and ethnic groups. The foundation for partnering with older Latinxs, in particular, began with our earliest cohort study, the Religious Orders Study (ROS) [34].…”