Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities

AbstractWhite matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant inGBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = −0.74, standard error (SE) = 0.13,P = 9.7 × 10−9].Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants inHTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10−6, false discovery rate  = 0.04).HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204 –364; β = 0.79, SE = 0.14,P = 9.4 × 10−8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare pro...

Source: Brain - October 9, 2021 Category: Neurology Source Type: research