Genome-wide association study of white matter hyperintensity volume in elderly persons without dementia

Abstract

Background: White matter hyperintensity has been correlated with cognitive disorders and its genetic predictors remain unclear. Here we conducted a genome-wide association study to identify novel genetic determinants that were correlated with white matter hyperintensity volume (WMHV) among non-demented elders. Methods: Three hundred and fifty non-Hispanic Caucasian subjects aged 55–80 years were included from the Alzheimer's Disease Neuroimaging Initiative cohort. Associations of WMHV with genetic polymorphisms were explored using multiple linear regression under an additive genetic model. Further studies were conducted to explore the influence of genetic variants on cognition-related phenotypes. Results: Rs7220676 near HS3ST3A1 and MIR548H3 genes was associated with WMHV levels at genome-wide significance (P = 2.96 × 10−8). Single nucleotide polymorphisms comprising rs9675262 (near HS3ST3A1 and MIR548H3 genes, P = 1.15 × 10−7), rs9820240 (in DCLK3 gene, P = 2.23 × 10−7), rs10916409 (near ISCA1P2 gene, P = 4.55 × 10−6), and rs540422 (in PICALM gene, P = 9.68 × 10−6) were identified as suggestive loci linked to WMHV levels. The minor allele of rs7220676 (C) showed association with lower log (WMHV) in a dose-dependent manner. Besides, rs7220676 was correlated with rates of cognitive decline assessed by Mini-mental State Examination and memory scores. Conclusions: A novel locus near HS3ST3A1 and MIR548H3 genes was associated with WMHV levels and it may be involved in neurodegenerative diseases.

Keywords

• White matter hyperintensity volume
• Cognition
• Genome-wide association study