Data from: Exome-chip association analysis of intracranial aneurysms

Objective: To investigate to what extent low-frequency genetic variants
(with minor allele frequencies <5%) affect the risk of intracranial
aneurysms (IA). Methods: 1056 IA patients and 2097 population-based
controls from the Netherlands were genotyped using the Illumina HumanExome
BeadChip. After quality control (QC) of samples and single nucleotide
variants (SNVs), we conducted a single variant analysis using Fisher’s
exact test. We also performed the variable threshold (VT) and the sequence
kernel association tests (SKAT) at different minor allele count (MAC)
thresholds of ±5 and ±0 to test the hypothesis that multiple variants
within the same gene are associated with IA risk. Significant results were
tested in a replication cohort of 425 IA patients and 311 controls, and
results of the two cohorts were combined in a meta-analysis. Results:
After QC, 995 IA patients and 2080 controls remained for further analysis.
The single variant analysis comprising 46,534 SNVs did not identify
significant loci at the genome-wide level. The gene-based tests showed a
statistically significant association for FBLN2 (best p=1x10-6 for the VT
test, MAC±5). Associations were not statistically significant in the
independent but smaller replication cohort (p±0.57), but became slightly
stronger in a meta-analysis of the two cohorts (best p=4.8x10-7 for the
SKAT, MAC>1). Conclusion: Gene-based tests indicated an association
for FBLN2, a gene encoding an extracellular matrix protein implicated in
vascular wall remodeling, but independent validation in larger cohorts is
warranted. We did not identify any significant associations for single
low-frequency genetic variants.