Abstract WP53: Genetics of Cerebral White Matter Hyperintensities in Diverse Hispanic/Latino Adults

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Cerebral white matter hyperintensities (WMH) on magnetic resonance imaging are part of the spectrum of brain vascular injury accompanying aging and are associated with an increased risk of stroke and dementia. WMH burden is greater among Hispanic than non-Hispanics white (NHW) adults. WMH is highly heritable and genome-wide association studies (GWAS) in older community-dwelling NHW and African American (AA) individuals have identified several genetic loci. However, the genetic architecture of WMH in Hispanic/Latino adults remains largely unknown. We conducted GWAS and admixture mapping analyses of WMH volume in a sample of 2159 diverse Hispanic/Latino adults (mean age: 62.4 years; 66% women). The proportion of variance in WMH volume attributable to common and low frequency variants in our sample was 28.9%, similar to a previous estimate in NHW individuals (29%). No association reached genome-wide significance. The strongest association was for rs60690281 (P=9.3x10 -8 ). Accounting for population differences in linkage disequilibrium, we found evidence of transferability of 14 of the 27 known WMH loci. Interestingly, while there was no association of the chr10p14 locus, previously identified in AA, in our total sample, there was a suggestive association (P=0.08) in the Caribbean subgroup. Due to power limitations, we could not exclude transferability of the remaining loci. Multi-ancestry meta-analysis combining our GWAS results with those from GWAS of WMH in NHW and AA populations identified an additional locus on chr12q22 (P=1.8x10 -8 ) tagged by rs10859915, an expression QTL of AMDHD1 . Admixture mapping identified a novel locus on chr14q13.2, where counts of European ancestry at that locus were significantly associated with WMH volume (P=4.9x10 -7 ). This locus spans an 800 kb region containing RALGAPA1, with known impact on neuronal function and brain development; and INSM2, encoding a transcriptional repressor influencing glucose metabolism. Our study suggests that WMH loci previously identified in NHW and AA individuals are relevant to Hispanic/Latino adults. It demonstrates the power of the diverse Hispanic/Latino population to discover novel WMH loci and haplotypes, adding to our understanding of WMH genetic architecture.

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